U.S. patent application number 10/524486 was filed with the patent office on 2006-10-19 for 2-thio-substituted imidazole derivatives and their use in pharmaceutics.
This patent application is currently assigned to MERCKLE-GMBH. Invention is credited to Wolfgang Albrecht, Stefan Laufer, Hans-Gunter Striegel, Karola Tollmann.
Application Number | 20060235054 10/524486 |
Document ID | / |
Family ID | 31197117 |
Filed Date | 2006-10-19 |
United States Patent
Application |
20060235054 |
Kind Code |
A1 |
Laufer; Stefan ; et
al. |
October 19, 2006 |
2-Thio-substituted imidazole derivatives and their use in
pharmaceutics
Abstract
The invention relates to 2-thio-substituted imidazole
derivatives of the formula I ##STR1## in which the radicals
R.sup.1, R.sup.2 R.sup.3 and m are as defined in the description.
The compounds according to the invention have immunomodulating
and/or cytokine-release-inhibiting action and are therefore
suitable for treating disorders associated with a disturbed immune
system.
Inventors: |
Laufer; Stefan; (Bleubeuren,
DE) ; Striegel; Hans-Gunter; (Blaustein, DE) ;
Tollmann; Karola; (Brechen, DE) ; Albrecht;
Wolfgang; (Ulm, DE) |
Correspondence
Address: |
C. IRVIN MCCLELLAND;OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
MERCKLE-GMBH
Graf-Arco-Strasse 3
Ulm
DE
89079
|
Family ID: |
31197117 |
Appl. No.: |
10/524486 |
Filed: |
August 20, 2003 |
PCT Filed: |
August 20, 2003 |
PCT NO: |
PCT/EP03/09219 |
371 Date: |
November 17, 2005 |
Current U.S.
Class: |
514/341 ;
546/272.7 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 3/10 20180101; A61P 25/00 20180101; A61P 25/28 20180101; A61P
1/02 20180101; A61P 19/02 20180101; A61P 25/08 20180101; A61P 1/04
20180101; A61P 17/14 20180101; A61P 37/02 20180101; A61P 9/10
20180101; A61P 19/10 20180101; A61P 19/06 20180101; A61P 37/08
20180101; A61P 9/04 20180101; A61P 37/06 20180101; A61P 35/00
20180101; A61P 29/00 20180101; A61P 25/04 20180101; A61P 9/00
20180101; A61P 1/16 20180101; A61P 37/00 20180101; A61P 17/06
20180101; C07D 401/04 20130101; A61P 31/18 20180101 |
Class at
Publication: |
514/341 ;
546/272.7 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 20, 2002 |
DE |
102 38 045.7 |
Claims
1. A 2-thio-substituted imidazole derivative of the formula I:
##STR159## wherein R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.7-cycloalkyl or aryl which is unsubstituted or
substituted by a halogen atom, by C.sub.1-C.sub.6-alkyl or by
halo-C.sub.1-C.sub.6-alkyl; R.sup.2 is selected from the group
consisting of: a) aryl-C.sub.1-C.sub.4-alkyl, where the aryl
radical may have one, two or three substituents. independently of
one another, selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, halogen,
C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl and hydroxyl, and b)
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted by CN
or halogen, ##STR160## R.sup.3 is selected from the group
consisting of a) NR.sup.4R.sup.10, b) NR.sup.7COR.sup.10, c)
NR.sup.7COOR.sup.10, d) NR.sup.7CONR.sup.7R.sup.10, e)
NR.sup.7CONR.sup.7COR.sup.10, f) OR.sup.10, g) S(O).sub.mR.sup.10,
h) halogen, i) OH, j) N.sub.3, k) NH.sub.2, and l) SH, and wherein
R.sup.3 is not OH, halogen, C.sub.1-C.sub.6-alkylthio or
C.sub.1-C.sub.6-alkoxy, if R.sup.2 is phenyl-C.sub.1-C.sub.4-alkyl,
and the phenyl radical has a C.sub.1-C.sub.6-alkylsulfanyl,
C.sub.1-C.sub.6-alkylsulfinyl or C.sub.1-C.sub.6-alkylsulfonyl
substituent, R.sup.4 is H or a physiologically cleavable group,
R.sup.5 and R.sup.6, which may be identical or different, are H,
halogen, OH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkyl,
halo-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylsulfanyl,
NH.sub.2, C.sub.1-C.sub.6-alkylamino or
di-C.sub.1-C.sub.6-alkylamino, R.sup.7 is R.sup.4,
C.sub.1-C.sub.6-alkyl or benzyl, R.sup.10 is selected from the
group consisting of: ##STR161## f) C.sub.1-C.sub.6-alkyl which is
substituted by 2 or 3 phenyl groups, and g) trifluoromethyl, A is
straight-chain or branched C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene or C.sub.3-alkynylene, B is selected
from the group consisting of: ##STR162## f) OC.sub.1-C.sub.6-alkyl,
g) NR.sup.11R.sup.12, h) OH, i) halogen, and j)
C.sub.1-C.sub.6-alkylsulfanyl, R.sup.11 and R.sup.12, which may be
identical or different, are H, C.sub.1-C.sub.6-alkyl or phenyl, Hy
is a 3- to 10-membered, non-aromatic mono-, bi- or tricyclic
carbocycle, which may or may not be fused with a benzene ring, Ar
is a 5- or 6-membered aromatic heterocycle, which has 1, 2 or 3
hetero-atoms, independently of one another, selected from the group
consisting of O, S and N, and which may or may not be fused with a
benzene ring, Het is a 5- or 6-membered, non-aromatic heterocycle,
which has 1, 2 or 3 heteroatoms, independently of one another,
selected from the group consisting of O, S and N, which may or may
not be fused with a benzene ring, and which may or may not be
bridged bicyclically or tricyclically; m is 0, 1, or 2; n is 1, 2,
3, 4 or 5; and the tautomers, optical isomers and physiologically
acceptable salts thereof.
2. The imidazole derivative as claimed in claim 1 of the formula I,
wherein R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.7-cycloalkyl or aryl which may or may not be
substituted by a halogen atom; R.sup.2 is selected from the group
consisting of. a) aryl-C.sub.1-C.sub.4-alkyl, where the aryl
radical may have one, two or three substituents, independently of
one another, selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, halogen,
C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl and hydroxyl, b)
C.sub.1-C.sub.6-alkyl which may or may not be substituted by CN;
and c) C.sub.3-C.sub.7-cycloalkyl; R.sup.3 is selected from the
group consisting of: a) NR.sup.4R.sup.10, b) NR.sup.7COR.sup.10, c)
halogen, d) C.sub.1-C.sub.6-alkoxy, and e)
C.sub.1-C.sub.6-alkylthio, wherein R.sup.3 is not OH, halogen,
C.sub.1-C.sub.6-alkylthio or C.sub.1-C.sub.6-alkoxy, if R.sup.2 is
phenyl-C.sub.1-C.sub.4-alkyl, and the phenyl radical has a
C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl or
C.sub.1-C.sub.6-alkylsulfonyl substituent; R.sup.4 is H, R.sup.10
is ##STR163## or, if R.sup.3 is NR.sup.7COR.sup.10, is R.sup.8,
R.sup.5 and R.sup.6, which may be identical or different, are H,
halogen, OH, C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkyl, R.sup.7
is H, C.sub.1-C.sub.6-alkyl or benzyl, R.sup.8 is
C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.6-cycloalkyl or phenyl, where
the phenyl group may have one or two substituents, independently of
one another, selected from the group consisting of
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.4-alkoxy and halogen, A is
straight-chain or branched C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene or C.sub.3-alkynylene, and m is 0, 1 or
2 or a tautomer, an optic isomer or a physiologically acceptable
salt thereof.
3. The imidazole derivative as claimed in claim 1, wherein formula
I is represented by the structure for formula Ia: ##STR164## in
which R.sup.1, R.sup.2, R.sup.3 and m are as defined for the
structure of formula I.
4. The imidazole derivative as claimed in claim 1, wherein R.sup.3
is ##STR165## where A, R.sup.5 and R.sup.6 are as defined for the
structure of formula I.
5. The imidazole derivative as claimed in claim 1, wherein, in
formula I, R.sup.10 is selected from the group consisting of:
##STR166## where Ar is a 5- or 6-membered aromatic heterocycle,
which has a heteroatom selected from the group consisting of N, O
and S; A is C.sub.1-C.sub.3-alkylene, and may be substituted by a
phenyl radical, and R.sup.5 and R.sup.6 are H; ##STR167## where Het
is a 5- or 6-membered non-aromatic heterocycle, which has an O or N
heteroatom; A is C.sub.1-C.sub.3-alkylene, and R.sup.5 and R.sup.6
are H; ##STR168## where A is C.sub.1-C.sub.6-alkylene; R.sup.5 and
R.sup.6 are H, and Hy is cyclopentyl or cyclohexyl; d) cyclopentyl
or cyclohexyl; e) phenyl-C.sub.1-C.sub.6-alkyl, where the alkyl
radical may have an additional phenyl substituent; and f)
C.sub.2-C.sub.6-alkenyl which is substituted by phenyl.
6. The imidazole derivative as claimed in claim 1, wherein, in
formula I, R.sup.3 is A-B, and B is selected from the group
consisting of NR.sup.11R.sup.12, OC.sub.1-C.sub.6-alkyl and OH, and
A, R.sup.11 and R.sup.12 are as defined for formula I.
7. The imidazole derivative as claimed in claim 1, wherein, in
formula I, R.sup.3 is NR.sup.7COR.sup.8, where R.sup.8 is selected
from the group consisting of --O--C.sub.1-C.sub.4-alkylphenyl,
phenyl and C.sub.2-C.sub.6-alkenyl which is substituted by
phenyl.
8. The imidazole derivative as claimed in claim 1, wherein A is
C.sub.1-C.sub.2-alkylene.
9. The imidazole derivative as claimed in claim 1, wherein A is
ethylidene.
10. The imidazole derivative as claimed in claim 1, wherein R.sup.5
and R.sup.6 are H.
11. The imidazole derivative as claimed in claim 1, wherein R.sup.1
is halogen-substituted phenyl, CF.sub.3-substituted phenyl or
C.sub.1-C.sub.6-alkyl-substituted phenyl.
12. The imidazole derivative as claimed in claim 1, wherein R.sup.2
is benzyl or C.sub.1-C.sub.6-alkyl.
13. A pharmaceutical composition, comprising the imidazole
derivative as claimed in claim 1, and one or more pharmaceutically
acceptable carriers and/or additives.
14. (canceled)
15. A method for treating disorders associated with a disturbed
immune system, which comprises, administering, to a person in need
thereof, the imidazole derivative, as claimed in claim 1, in an
amount sufficient to have immunomodulating action and/or to inhibit
the release of cytokine.
Description
[0001] The present invention relates to 2-thio-substituted
imidazole derivatives having immunomodulating and
cytokine-release-inhibiting action, to pharmaceutical compositions
comprising these compounds and to their use in pharmacy.
[0002] Pharmacologically active imidazole compounds with
anti-inflammatory activity are already known. Thus, inter alia,
compounds having 4,5-di(hetero)arylimidazole moieties have been
examined more closely, and various pharmaceutical actions thereof
have been described. Also known are compounds which are substituted
in the 2-position. U.S. Pat. No. 4,585,771 discloses
4,5-diphenylimidazole derivatives which are substituted in the
2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical
and which have anti-inflammatory and antiallergic activity. U.S.
Pat. Nos. 4,528,298 and 4,402,960 describe
4,5-di(hetero)arylimidazole derivatives which are substituted in
the 2-position via a thio, sulfinyl or sulfonyl group by a phenyl,
pyridyl, N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical and
which have anti-inflammatory and antiallergic activity. U.S. Pat.
Nos. 4,461,770, 4,528,298 and 4,584,310 (EP 004 648 A) describe
4-(5-aryl)-5-(4-heteroaryl)imidazole derivatives which are
substituted in the 2-position via a thio, sulfinyl or sulfonyl
group by a substituted or unsubstituted aliphatic hydrocarbon and
which, inter alia, have anti-inflammatory action. Imidazole
compounds having immunomodulating and cytokine-release-inhibiting
action are described in WO 02/066458, WO 02/076951 and DE 102 22
103. Further imidazole compounds having anti-inflammatory action
are described in WO 96/03387, EP 005 545 (U.S. Pat. Nos. 4,440,776;
4,355,039; 4,269,847), EP 236 628 (U.S. Pat. No. 4,686,231), DE 35
04 678, U.S. Pat. No. 4,190,666, U.S. Pat. No. 4,402,960 and U.S.
Pat. No. 4,585,771. EP 372 445 (U.S. Pat. No. 5,318,984; U.S. Pat.
No. 5,166,214) and U.S. Pat. No. 5,364,875 describe imidazole
compounds having antihypercholesterolemic activity.
[0003] WO 00/17192 (DE 198 42 833) relates to
4-heteroaryl-5-phenylimidazole derivatives which are substituted in
the 2-position by a phenylalkylthio group. These compounds act as
anti-inflammatories and inhibitors of cytokine release. WO 99/03837
and WO 93/14081 describe 2-substituted imidazoles which inhibit the
synthesis of a number of inflammatory cytokines. The compounds
described in WO 93/14081 have in the 2-position, attached via a
sulfur atom, a phosphorus-containing substituent or an aryl or
heteroaryl substituent. WO 91/10662 and WO 91/13876 describe
imidazole derivatives which inhibit the acyl-coenzyme
A:cholesterol-O-acyl transferase and binding of thromboxane
TxA.sub.2. WO 95/00501 describes imidazole derivatives which can be
used as cyclooxygenase inhibitors.
[0004] J. Med. Chem. 1996, 39, 3927-37 describes compounds having
5-lipoxygenase- and cyclooxygenase-inhibiting action,
2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl-5-(pyrid-4-yl)imidazole
also having cytokine-inhibiting action.
[0005] Further 2-thio-substituted imidazole derivatives are
described in JP 01-040 467, SU 1 415 725, Acta Chim. 1969, 61,
69-77, J. prakt. Chem. 1972, 314, 785-792 and DE 101 14 775, Indian
J. Chem., Sect. B, 1983, 22B(3), 268-269, Bioorganic &
Medicinal Chem. Lett., Vol 5, No. 2, 177-180, 1995, Phosphorus
Sulfur 1988, 35(1-2), 83-88, Arch. Biochem. Biophys. Vol. 297,
258-264, 1992, J. Med. Chem. 1995, 38, 1067-1083, Helv. Chim. Acta
82, 1999, 290-296, Helv. Chim. Acta 81, 1998, 1585-1595.
[0006] In spite of the fact that numerous compounds are known,
there is therefore still a need for compounds having
anti-inflammatory action which inhibit cytokine release.
[0007] It is an object of the invention to provide such
compounds.
[0008] Surprisingly, it has now been found that certain
2-substituted imidazole derivatives have high immunomodulating
and/or cytokine-release inhibiting activity.
[0009] Accordingly, the present invention provides
2-thio-substituted imidazole derivatives of the formula I ##STR2##
in which [0010] R.sup.1 is C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.7-cycloalkyl or aryl which is unsubstituted or
substituted by a halogen atom, by C.sub.1-C.sub.6-alkyl or by
halo-C.sub.1-C.sub.6-alkyl; [0011] R.sup.2 is selected from the
group consisting of [0012] a) aryl-C.sub.1-C.sub.4-alkyl, where the
aryl radical may have one, two or three substituents independently
of one another selected from the group consisting of
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, halogen,
C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl,
C.sub.1-C.sub.6-alkylsulfonyl and hydroxyl, and [0013] b)
C.sub.1-C.sub.6-alkyl which is unsubstituted or substituted by CN
or halogen; ##STR3## [0014] R.sup.3 is selected from the group
consisting of [0015] a) NR.sup.4R.sup.10; [0016] b)
NR.sup.7COR.sup.10; [0017] c) NR.sup.7COOR.sup.10; [0018] d)
NR.sup.7CONR.sup.7R.sup.10; [0019] e) NR.sup.7CONR.sup.7COR.sup.10;
[0020] f) OR.sup.10; [0021] g) S(O).sub.mR.sup.10; [0022] h)
halogen; [0023] i) OH; [0024] j) N.sub.3 [0025] k) NH.sub.2 [0026]
l) SH; [0027] where R.sup.3 is not OH, halogen,
C.sub.1-C.sub.6-alkylthio or C.sub.1-C.sub.6-alkoxy if R.sup.2 is
phenyl-C.sub.1-C.sub.4-alkyl and the phenyl radical has a
C.sub.1-C.sub.6-alkylsulfanyl, C.sub.1-C.sub.6-alkylsulfinyl or
C.sub.1-C.sub.6-alkylsulfonyl substituent; [0028] R.sup.4 is H or a
physiologically cleavable group, [0029] R.sup.5 and R.sup.6, which
may be identical or different, are H, halogen, OH,
C.sub.1-C.sub.6-alkoxy, C.sub.1-C.sub.6-alkyl,
halo-C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkylsulfanyl,
NH.sub.2, C.sub.1-C.sub.6-alkylamino or
di-C.sub.1-C.sub.6-alkylamino; [0030] R.sup.7 is R.sup.4,
C.sub.1-C.sub.6-alkyl or benzyl; [0031] R.sup.10 has one of the
meanings below: ##STR4## [0032] f) C.sub.1-C.sub.6-alkyl which is
substituted by 2 or 3 phenyl groups; [0033] g) trifluoromethyl (in
particular, if R.sup.3 is one of the radicals b) to f)) [0034] A is
straight-chain or branched C.sub.1-C.sub.6-alkylene,
C.sub.2-C.sub.6-alkenylene or C.sub.3-alkynylene; [0035] B is
selected from the group consisting of ##STR5## [0036] f)
OC.sub.1-C.sub.6-alkyl; [0037] g) NR.sup.11R.sup.12; [0038] h) OH;
[0039] i) halogen; [0040] j) C.sub.1-C.sub.6-alkylsulfanyl [0041]
R.sup.11 and R.sup.12, which may be identical or different, are H,
C.sub.1-C.sub.6-alkyl or phenyl; [0042] Hy is a 3- to 10-membered
non-aromatic mono-, bi- or tricyclic carbocycle which may or may
not be fused with a benzene ring; [0043] Ar is a 5- or 6-membered
aromatic heterocycle which has 1, 2 or 3 hetero-atoms independently
of one another selected from the group consisting of O, S and N and
which may or may not be fused with a benzene ring; [0044] Het is a
5- or 6-membered non-aromatic heterocycle which has 1, 2 or 3
heteroatoms independently of one another selected from the group
consisting of O, S and N, which may or may not be fused with a
benzene ring and which may or may not be bridged bicyclically or
tricyclically; [0045] m is 0, 1 or 2; [0046] n is 1, 2, 3,4 or 5;
and the tautomers, optic isomers and physiologically acceptable
salts thereof.
[0047] If the compounds according to the invention have centers of
asymmetry, the scope of the invention includes both racemates and
optical isomers (enantiomers, diastereomers). In the compounds
according to the invention, the following tautomeric equilibrium
may be present: ##STR6##
[0048] The invention embraces both tautomeric forms.
[0049] The invention also embraces the physiologically acceptable
salts of the compounds of the formula I. In the present case, these
are in particular acid addition salts. For acid addition salts,
what is used are inorganic acids, such as hydrochloric acid,
sulfuric acid or phosphoric acid, or organic acids, such as
tartaric acid, citric acid, maleic acid, fumaric acid, malic acid,
mandelic acid, ascorbic acid, gluconic acid and the like.
[0050] The term "alkyl" (also in combination with other groups,
such as phenylalkyl, alkylsulfonyl, alkoxy, etc.) embraces
straight-chain and branched alkyl groups having 1 to 6 or 1 to 4
carbon atoms, such as methyl, ethyl, n- and isopropyl, n-, iso- and
t-butyl, sec-butyl, n-pentyl, isoamyl, neopentyl and n-hexyl. This
applies correspondingly to "C.sub.1-C.sub.6-alkylene".
[0051] The term "carbocycle" embraces saturated or unsaturated
non-aromatic monocyclic, bicyclic and tricyclic hydrocarbons. The
hydrocarbons can be fused with one or two benzene rings. Monocyclic
hydrocarbons are C.sub.3-C.sub.6-cycloalkyl, such as cyclopropyl,
cyclopentyl, cyclohexyl. Examples of bi- and tricyclic hydrocarbons
and benzo-fused carbocycles are indanyl, decalinyl, tetralinyl,
fluorenyl, dihydroanthracenyl, dibenzosuberenyl, norbornyl or
adamantyl. Examples of substituted carbocycles are
methylcyclopropyl or methylcyclohexyl. Preference is given to
unsubstituted radicals.
[0052] The term "aryl" embraces aromatic ring systems, such as
phenyl or naphthyl.
[0053] The term "halogen" represents a fluorine, chlorine, bromine
or iodine atom, in particular a fluorine or chlorine atom.
[0054] The term "halo-C.sub.1-C.sub.6-alkyl" embraces mono- or
polyhalogenated straight-chain and branched alkyl groups having 1
to 6 and in particular 1 to 4 carbon atoms. Preferably, 1, 2, 3, 4
or 5 halogen atoms are present. Preferred halogen atoms are F and
Cl. Examples of halo-C.sub.1-C.sub.6-alkyl are --CH.sub.2Cl,
--CH.sub.2CH.sub.2Cl, --CH.sub.2CCl.sub.3, --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --CH.sub.2CF.sub.3 and --CF.sub.2CF.sub.3. CF.sub.3 is
preferred.
[0055] A physiologically cleavable group is a group which can be
cleaved from the remainder of the molecule under physiological
conditions, enzymatically or chemically. Examples are --COR.sup.14,
--CO.sub.2R.sup.14, --CONH.sub.2, --CONHR.sup.14,
--CHR.sup.16--OR.sup.14, --CHR.sup.16--O--COR.sup.14,
--COC(R.sup.16).sub.2--OH, --COR.sup.15, SO.sub.2R.sup.15 and
--SO.sub.2R.sup.14, where R.sup.14 is C.sub.1-C.sub.6-alkyl or
CF.sub.3, R.sup.15 is phenyl or tolyl (in particular p-tolyl) and
R.sup.16 is H or C.sub.1-C.sub.6-alkyl.
[0056] The aromatic 5- or 6-membered heterocycle is in particular
unsubstituted (R.sup.5, R.sup.6.dbd.H) or substituted 2-pyridyl,
3-pyridyl, 4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, thiazolyl,
imidazolyl, oxazolyl, isothiazolyl, pyrazolyl, isoxazolyl,
triazolyl or pyrimidyl. Preferred substituents are one or two
groups independently of one another selected from the group
consisting of halogen, in particular Cl, and C.sub.1-C.sub.6-alkyl.
The substituent(s) are attached to a carbon atom or a nitrogen atom
of the aromatic radical. Preferred are unsubstituted radicals.
Examples of substituted radicals are chlorothienyl, in particular
5-chlorothien-2-yl, chlorofuryl, in particular 5-chlorofur-2-yl,
examples of fused radicals are benzofuranyl, benzothiazolyl and
benzothiophene.
[0057] The non-aromatic 5- or 6-membered heterocycle may be
saturated or unsaturated. It is preferably unsubstituted or
substituted tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,
N-methylpyrrolidinyl, N-ethylpyrrolidinyl, piperazinyl or
morpholinyl, where the heterocycle may be attached via a nitrogen
heteroatom or a ring carbon atom or may be substituted. Preferred
substituents are one or two radicals independently of one another
selected from the group consisting of halogen, in particular Cl,
and C.sub.1-C.sub.6-alkyl. Preference is given to unsubstituted
radicals. ##STR7## is substituted or unsubstituted cyclopropyl,
cyclobutyl, cycloheptyl and, in particular, cyclopentyl and
cyclohexyl. R.sup.5 and R.sup.6 are preferably independently of one
another H, halogen or C.sub.1-C.sub.6-alkyl. Examples of
substituted cycloalkyl groups are methylcyclopropyl or
methylcyclohexyl. Preference is given to unsubstituted
radicals.
[0058] Phenyl-C.sub.1-C.sub.4-alkyl is in particular benzyl,
1-phenylethyl or 2-phenylethyl.
[0059] R.sup.1 is preferably a phenyl radical and in particular a
halogen-, CF.sub.3-- or C.sub.1-C.sub.6-alkyl-substituted phenyl
radical, a fluorine-substituted phenyl radical being particularly
preferred. The substituent is preferably in the 3- and in
particular in the 4-position. Examples of substituted phenyl
radicals are 4-fluorophenyl, 2,4-difluorophenyl, 3-trifluoromethyl,
3-tolyl or 3-chlorophenyl.
[0060] R.sup.2 is preferably a benzyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.4-C.sub.7-methylcycloalkyl or C.sub.1-C.sub.6-alkyl radical,
where the phenyl group of the benzyl radical may be substituted as
indicated above. Preferred substituents of the phenyl group of the
benzyl radical are C.sub.1-C.sub.6-alkylsulfanyl,
C.sub.1-C.sub.6-alkylsulfinyl and C.sub.1-C.sub.6-alkylsulfonyl.
Examples of R.sup.2 are CH.sub.3, CH.sub.3CH.sub.2,
(CH.sub.3).sub.2CH, CH.sub.2CN, CH.sub.2CF.sub.3, CF.sub.3 and
cyclopropyl.
[0061] R.sup.3 is preferably the radical of the formula ##STR8## in
which R.sup.4, R.sup.5 and R.sup.6 and also A are as defined above.
R.sup.5 and R.sup.6 are preferably H, methyl, methoxy or chlorine.
If the phenyl ring of this group is substituted, the radicals
R.sup.5 and R.sup.6 are preferably located in the 3- and/or
4-position.
[0062] Furthermore, R.sup.3 is preferably [0063] a)
NR.sup.4R.sup.10, where R.sup.10 is cyclopropyl, cyclopropylmethyl,
cyclopentyl, cyclohexyl or cycloheptyl; [0064] b) NR.sup.4R.sup.10,
where R.sup.10 is C.sub.1-C.sub.6-alkyl, in particular methyl,
ethyl or isopropyl, or is 3,3-diphenylpropyl or
1,3-diphenylprop-2-yl; [0065] c) NR.sup.4R.sup.10, where R.sup.10
is A-B and B is OH, C.sub.1-C.sub.6-alkyoxy, NR.sup.11R.sup.12 or
phenyl; [0066] d) NR.sup.7COR.sup.10, where R.sup.10 is A-B and B
is phenyl; [0067] e) NR.sup.7COOR.sup.10, where R.sup.10 is
C.sub.1-C.sub.6-alkyl.
[0068] A is preferably C.sub.1-C.sub.2-alkylene and in particular
ethylidene.
[0069] m is preferably 0.
[0070] A particularly preferred embodiment are the compounds of the
formula I in which R.sup.1 is 4-fluorophenyl, R.sup.2 is
C.sub.1-C.sub.6-alkyl or benzyl, where the phenyl group of the
benzyl radical may be substituted as indicated above; R.sup.3 is
the radical of the formula ##STR9## where R.sup.4, R.sup.5, R.sup.6
and A are as defined above, and m is 0.
[0071] A further preferred embodiment are compounds of the formula
I in which R.sup.2 is C.sub.1-C.sub.6-alkyl, in particular methyl,
and R.sup.1 is halophenyl or halo-C.sub.1-C.sub.6-alkylphenyl, in
particular 4-fluorophenyl, 2,4-difluorophenyl,
4-trifluoromethylphenyl or 3-trifluoromethylphenyl. R.sup.3 is then
preferably as defined below: [0072] a) halogen, in particular F or
Cl; [0073] b) OH or O C.sub.1-C.sub.6-alkyl, in particular methoxy
and isopropoxy, [0074] c) phenylamino; [0075] d) phenyl group by
phenyl- or naphthyl-C.sub.1-C.sub.4-alkylamino, 1 or 2 halogen, in
particular F or Cl, C.sub.1-C.sub.6-alkoxy or C.sub.1-C.sub.6-alkyl
may be substituted. The amino group may additionally be substituted
by C.sub.1-C.sub.6-alkyl. Examples of such radicals are
benzylamino, 4-methoxybenzylamino, 4-methylbenzylamino,
4-chlorobenzylamino, 3,4-dichlorobenzylamino, 2-phenylethylamino,
1-phenylethylamino, 1-naphth-1-yl-amino 1-naphth-2-ylamino;
1-phenylprop-3-ylamino, 3-phenylpropylamino,
1-(4-isobutylphenyl)ethylamino; ##STR10## [0076] in which A is
C.sub.1-C.sub.2-alkylene, R.sup.5 and R.sup.6 are H and ##STR11##
[0077] is thienyl, furyl, 2-, 3- or 4-pyridyl, thiazolyl, oxazolyl,
benzothiophenyl or benzofuranyl, where the heterocyclic radicals
may be substituted by halogen, in particular F or Cl, or
C.sub.1-C.sub.6-alkyl. ##STR12## [0078] in which A, R.sup.5,
R.sup.6 and ##STR13## [0079] are as defined under e). [0080] g)
NH--C.sub.1-C.sub.6-Alkyl which is substituted by 2 or 3 phenyl
groups, for example 3,3-diphenylpropylamino,
1,3-diphenylprop-2-ylamino; ##STR14## [0081] in which A is
C.sub.1-C.sub.2-alkylene, R.sup.5 and R.sup.6 are H and ##STR15##
is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidine, N-methyl- or
N-ethylpyrrolidine; ##STR16## [0082] in which R.sup.5, R.sup.6 and
##STR17## are as defined under h); [0083] j) --NH--COOR.sup.10, in
which R.sup.10 is C.sub.3-C.sub.6-cycloalkyl; [0084] k)
--NH--CO--NHR.sup.1.beta., in which R.sup.10 is
C.sub.3-C.sub.6-cycloalkyl; [0085] l) --NH--COR.sup.10, in which
R.sup.10 is C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.4-alkyl, for
example cyclopentylmethyl, cyclohexylmethyl; [0086] m) NH--CONH CO
phenyl; [0087] n) -A-C.sub.3-C.sub.6-cycloalkyl, in which A is
C.sub.1-C.sub.2-alkylene, for example cyclopentylmethylamino,
cyclohexylmethylamino.
[0088] The compounds according to the invention can be prepared in
a corresponding manner according to the processes described in the
state of the art mentioned at the outset, in particular WO
00/17192. The preparation according to the following two-step
process has been found to be particularly expedient. In the first
step, a substituted imidazole-2-thione of the formula II is
initially prepared. In the second step, this is then reacted such
that the 2-thio-substituted imidazole derivatives of the formula I
are obtained with introduction of the desired substituent R.sup.2.
##STR18##
[0089] 1) Preparation of the imidazole-2-thione
[0090] Imidazole-2-thiones where R.sup.3.dbd.H, halogen (Br, Cl,
F), O-alkyl or S-alkyl are prepared according to process A or B. By
way of example, process A is illustrated for compounds in which
R.sup.1 is 4-fluorophenyl and R.sup.3 is H, process B is
illustrated for compounds in which R.sup.1 is 4-fluorophenyl and
R.sup.3 is Cl, (25a), F (25b) or O-alkyl (25c, 25d) (the numbers in
brackets refer to the numbers of the examples). 2-Thio-substituted
imidazole derivatives where R.sup.3.dbd.NR.sup.4R.sup.10 are not
prepared from the corresponding imidazole-2-thiones where
R.sup.3.dbd.NR.sup.4R.sup.10 but in a different manner according to
process C. 2-Thio-substituted imidazole derivatives where
R.sup.3.dbd.O-alkyl or S-alkyl can be prepared both according to
process C and according to process B.
[0091] Process A
[0092] The synthesis of the substituted imidazole-2-thiones where
R.sup.3.dbd.H is carried out according to the course of the
reaction of scheme 1, using ethyl isonicotinate and
4-fluorophenylacetonitrile as starting materials.
[0093] The starting materials are converted in a condensation
reaction with the aid of metallic sodium in an alcohol, for example
ethanol, into 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone
(IIIa). The cyano group is then removed by hydrolysis, for example
with hydrobromic acid, and decarboxylation, giving
2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (IVa). In the next step,
IVa is converted by treatment with ammonium chloride/sodium acetate
in an alcoholic solvent, such as methanol, into the oxime (Va). By
reaction with p-toluenesulfonyl chloride in pyridine, the latter is
converted into the tosylate (VIa). From the tosylate, the thione
compound (IIa) is obtained by treatment with sodium ethoxide and
reaction of the azirene intermediate formed with potassium
thiocyanate. ##STR19##
[0094] Process B:
[0095] The preparation of the compounds according to the invention
in which the pyridine radical has a halogen, O-alkyl or S-alkyl
substituent is carried out according to scheme 2 via corresponding
2-halopyridyl-substituted imidazolthiones (process B). The
preparation of these imidazolthiones is illustrated using the
2-fluoro-substituted pyridinine compound (R.sup.3=2-F) where
R.sup.1=p-fluorophenyl as an example. Imidazolthiones carrying, in
position 4, alkyl and cycloalkyl radicals
(R.sup.1.dbd.C.sub.1-C.sub.4-alkyl, C.sub.3-C.sub.7-cycloalkyl) are
obtained in an analogous manner starting with the appropriately
substituted 2-fluoro-.gamma.-picoline ketones. ##STR20##
[0096] .gamma.-Picoline (R.sup.3.dbd.H) and the
halogen-(R.sup.3.dbd.F, Cl, Br, I), methoxy-(R.sup.3.dbd.OCH.sub.3)
and methylthio-(24, R.sup.3.dbd.SCH.sub.3) substituted
.gamma.-picolines are lithiated in the .gamma.-methyl group with
exclusion of moisture, in solvents suitable for this purpose, such
as hydrocarbons, ethers and mixtures thereof (for example hexane,
tetrahydrofuran, ethylene glycol, dimethyl ether), using lithium
diisopropylamide (LDA) and then condensed with suitable carboxylic
acid derivatives (R.sup.1--COOR, R.sup.1--CONR.sub.2, R.sup.1--CN).
Here, the amides of the N,O-dimethylhydroxylamine
(R.sup.1--CONCH.sub.3(OCH.sub.3), 20) have been found to be
particularly suitable. Using nitrites and bases, for example amyl
nitrite /sodium methoxide, or using alkali metal nitrite and acid,
the .gamma.-picolyl ketones (IVb) formed are nitrosated in the
.gamma.-picolyl position. The reaction of the .gamma.-picolyl
ketone, dissolved in glacial acetic acid, with aqueous sodium
nitrite solution has been found to be particularly advantageous.
During this reaction, the nitrosoketones are converted completely
into the tautomeric oxime ketones (VIIb).
[0097] The oxime ketones are reduced in alcoholic solution in the
presence of hydrogen and mineral acids, for example HCl, using
palladium-on-carbon, to give the ammonium salts of the amine
ketones (VIIIb) (23b).
[0098] Alternatively, other oxime ketones can be reduced in
alcoholic solution in the presence of mineral acids, for example
H.sub.2SO.sub.4, using zinc dust, to give the corresponding
ammonium ketones (23f).
[0099] These ammonium ketone compounds afford, after action of
alkali metal thiocyanates, for example potassium thiocyanate in dry
dimethylformamide (DMF) with heating under reflux, the
imidazolethiones of the formula IIb where R.sup.3.dbd.F, Cl, Br,
O-alkyl or S-alkyl, as yellow solids (24b).
[0100] The preparation of the compounds according to the invention
in which the pyridine radical has an ether (R.sup.3.dbd.OR.sup.10),
thioether (R.sup.3.dbd.SR.sup.10) or amino substituent
(R.sup.3.dbd.NR.sup.4R.sup.10) is carried out according to scheme 4
or scheme 5, via corresponding 2-halopyridyl-substituted
imidazolethiones (process C, see below).
[0101] 2) Preparation of the 2-thioimidazole Compound
[0102] The imidazolethione compounds of the formula II obtained
according to process A or B are, by substitution of the sulfur atom
in the 2-position, converted into the compounds of the formula I
according to the invention. The substitutions, as shown in an
exemplary manner for some compounds in scheme 3, are carried out in
a known manner using a nucleophilic substitution reaction. Here,
the compound IIa or IIb is reacted with R.sup.2--X in an inert
polar solvent, such as an alcohol. X is an easily exchangeable
group, such as Hal, in particular Cl, Br, I, methylsulfonyl, tosyl,
etc. Suitable processes are known to the person skilled in the art
and described, for example, in WO 00/17192, EP 0 372 445 and U.S.
Pat. No. 4,440,776. The compounds R.sup.2--X are known or can be
prepared by known processes as described, for example, in WO
00/17192. ##STR21##
[0103] Process C:
[0104] Compounds according to the invention in which R.sup.3 is an
amino substituent (R.sup.3.dbd.NR.sup.4R.sup.10) are prepared from
2-thioimidazoles using 4(5)-(2-halopyridin-4-yl) substitution. The
process (process C) is illustrated in scheme 4 using the
2-benzylamino (R.sup.3.dbd.NH--CH.sub.2Ph) where
R.sup.1=p-fluorophenyl as an example (25f).
[0105] The starting materials (Ib) can be prepared by the process
described above. ##STR22## ##STR23##
[0106] The reaction is expediently carried out in the amine in
question, which is preferably employed in an amount of from 5 to 20
mole equivalents per mole equivalent of the compound (Ib). The
reaction temperature is generally in the range from 100 to
200.degree. C. If desired, it is also possible to use an inert
solvent, such as dioxane, dimethylformamide, diethylacetamide,
tetraethylurea, methylpyrrolidone, etc., and appropriate additives,
such as alkali metal carbonates or monovalent copper halides (to
neutralize acid equivalents released or to catalyze the elimination
of halogen). The compounds according to the invention in which
R.sup.3 is an alkoxy substituent or alkylthio substituent
(R.sup.3.dbd.O--C.sub.1-C.sub.6-alkyl, S--C.sub.1-C.sub.6-alkyl)
can not only be prepared by process B (starting with appropriately
substituted picolines) but also by process C, starting with the
4(5)-(2-halopyridin-4-yl)-substituted 2-thioimidazoles.
[0107] Process D:
[0108] The compounds according to the invention in which R.sup.3 is
an alkoxy substituent (R.sup.3.dbd.O--C.sub.1-C.sub.6-alkyl) can
not only be prepared by process B or C, but also by process D,
starting with the 4(5)-(2-halopyridin-4-yl)-substituted
2-thioimidazoles. The process is illustrated in scheme 5, using the
2-isopropyloxypyridinine compounds
(R.sup.3.dbd.OCH(CH.sub.3).sub.2) where R.sup.1=p-fluorophenyl as
an example.
[0109] The starting materials (Ib) can be prepared by the processes
described above. ##STR24##
[0110] The reaction is expediently carried out in the alcohol,
which is preferably used in an amount of from 5 to 20 mole
equivalents per mole equivalent of the compound (Ib), in the case
of lower alcohols also up to one hundred mole equivalents, in the
presence of a strong acid, such as HCl or trifluoroacetic acid,
methanesulfonic acid, etc. The reaction temperature is generally
within the boiling range of the lower alcohols, in the case of
higher alcohols in the range from 100 to 200.degree. C. It has been
found to be favorable, for example, to saturate the alcohol with
gaseous HCl, or to re-saturate during the reaction.
[0111] Alternatively, the exchange of fluorine for alkoxy in the
2-position of the pyridyl substituent can be carried out at an
earlier stage in the synthesis, for example at the stage of the
oxime ketones or the amine ketones. In these cases, the reactions
proceed under conditions comparable to those just described for
intermediate Ib (22c).
[0112] Processes E, F and G:
[0113] The compounds according to the invention in which R.sup.3 is
an amido substituent (R.sup.3.dbd.NR.sup.7COR.sup.10) are, firstly,
prepared from the 4(5)-(2-halopyridin-4-yl)-substituted
2-thioimidazoles. The process (process E) is illustrated in scheme
6.1 using the 2-benzoylamido (R.sup.3.dbd.NH--COPh) where
R.sup.1=p-fluorophenyl as an example. Secondly, after the
hydrolysis of the amides to the amine-substituted
(R.sup.3.dbd.NR.sup.7H, NHR.sup.10) 2-thioimidazoles and their
re-acylation or derivatization to amides, ureas and urethanes,
further amido substituents may be obtained (process F). This is
illustrated in scheme 6.2. Thirdly, 2-aminopyridine precursor
compounds may be obtained from 4(5)-(2-halopyridin-4-yl) compounds
via the 4(5)-(2-azidopyridin-4-yl) compounds (process G). In this
variant, the halogen is substituted nucleophilically by an alkali
metal azide, and the azide group is then converted by reduction
methods into the amino group, see scheme 6.3.
[0114] Process H:
[0115] This interesting variant also allows access to alkylated
amines from aldehyde and ketone precursors. If the conversion of
the azide group into the amino group is carried out under
hydrogenation conditions using a hydrogenation catalyst in the
presence of these aldehydes and ketones, alkylated amines where
R.sup.3.dbd.NHCH.sub.2--B or NHCH(alkyl)-B are obtained (process H.
scheme 6.4). The same result is obtained when the azide is cleaved
with a phosphine to give the phosphimide, and these imides obtained
after an aza-Wittig reaction with an aldehyde (or ketone) are
reduced to the amines using complex hydrides (process H, scheme
6.5).
[0116] The starting materials (Ib) can be prepared by the processes
described above. ##STR25##
[0117] The reaction is expediently carried out in the amide in
question, which is preferably employed in an amount of from 5 to 20
mole equivalents per mole equivalent of the compound (Ib). The
reaction temperature is generally in the range from 100 to
200.degree. C. If desired, it is also possible to use an inert
solvent, such as dioxane, dimethylformamide, diethylacetamide,
tetraethylurea, methylpyrrolidone, etc., and appropriate additives,
such as alkali metal carbonates or monovalent copper halides (to
neutralize acid equivalents released or to catalyze the elimination
of halogen).
[0118] The 2-aminopyridine compounds can be obtained from
2-amidoacylpyridines by hydrolysis (6.2) or else by azide
substitution of the 2-fluoro compounds and subsequent reduction of
the 2-azidopyridines (6.3), for example by hydrogenation on
palladium-on-carbon in alcoholic solvents. ##STR26## ##STR27##
[0119] Further conversions of the amines obtained (Ik, Id) by
derivatization are possible (process F). What is used are reactions
of the amines Id and Ik both with acid anhydrides and acid
chlorides to give further amides, and also reactions with
chloroformic esters to give urethanes, with isocyanates to give
ureas and with acyl isocyanates to give acylureas. These formations
of derivatives are illustrated in scheme 7. ##STR28##
[0120] In vitro and in vivo, the compounds according to the
invention show immunomodulating and cytokine-release inhibiting
action. Cytokines are proteins such as TNF-.alpha. and IL-.beta.
which play an important role in numerous inflammatory disorders.
The compounds according to the invention are, by virtue of their
cytokine-release-inhibiting action, suitable for treating disorders
which are associated with a disturbance of the immune system. They
are suitable, for example, for treating autoimmune disorders,
cancer, rheumatoid arthritis, gout, septic shock, osteoporosis,
neuropathic pain, the spread of HIV, HIV dementia, viral
myocarditis, insulin-dependent diabetes, periodontal disorders,
restenosis, alopecia, T-cell depletion associated with HIV
infections or AIDS, psoriasis, acute pancreatitis, rejection
reactions of allogenic transplants, allergic pneumonia,
arteriosclerosis, multiple sclerosis, cachexia, Alzheimer's
disease, stroke, ictus, colitis ulcerosa, morbus Crohn,
inflammatory bowel disease (IBD), ischemia, congestive heart
failure, pulmonary fibrosis, hepatitis, glioblastoma,
Guillain-Barre syndrome, systemic lupus erythematodes, adult
respiratory distress syndrome (ARDS) and respiratory distress
syndrome.
[0121] The compounds according to the invention can be administered
either as individual therapeutically active compounds or as
mixtures with other therapeutically active compounds. The compounds
can be administered on their own; in general, however, they are
formulated and administered in the form of pharmaceutical
compositions, i.e. as mixtures of the active compounds with
suitable pharmaceutical carriers or diluents. The compounds or
compositions can be administered orally or parenterally;
preferably, they are administered in oral dosage forms.
[0122] The type of pharmaceutical composition or carrier or diluent
depends on the desired administration form. Oral compositions, for
example, can be present as tablets or capsules and may comprise
customary excipients, such as binders (for example syrup, gum
arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone),
fillers (for example lactose, sugar, cornstarch, calcium phosphate,
sorbitol or glycerol), glidants (for example magnesium stearate,
talc, polyethylene glycol or silica), disintegrants (for example
starch) or wetting agents (for example sodium lauryl sulfate).
Liquid oral preparations can assume the form of aqueous or oily
suspensions, solutions, emulsions, syrups, elixirs or sprays and
the like. They can also be present as a dry powder which is
reconstituted using water or another suitable carrier. Such liquid
preparations may comprise customary additives, for example
suspending agents, flavors, diluents or emulsifiers. For parenteral
administration, it is possible to use solutions or suspensions with
customary pharmaceutical carriers.
[0123] The compounds or compositions according to the invention can
be administered to mammals (man or animal) in a dose of from about
0.5 mg to 100 mg per kg of body weight per day. They may be
administered in one individual dose or in a plurality of doses. The
activity spectrum of the compounds as inhibitors of cytokine
release was examined using the test systems below, as described by
C. Donat and S. Laufer in Arch. Pharm. Pharm. Med. Chem. 333,
Suppl. 1, 1-40. 2000.
[0124] In Vitro Test with Human Whole Blood
[0125] The test substance is added to samples of human
potassium-EDTA whole blood (of 400 .mu.l each) and the samples are
preincubated in a CO.sub.2 incubator (5% CO.sub.2; 95%
moisture-saturated air) at 37.degree. C. for 15 min. The samples
are then stimulated with 1 .mu.g/ml of LPS (E. coli 026:B6) at
37.degree. C. in a CO.sub.2 incubator (5% CO.sub.2; 95%
moisture-saturated air) for 4 hours. The reaction is stopped by
placing the samples on ice, adding DPBS buffer and then
centrifuging at 1000 g for 15 min. The amount of IL-1.beta. and
TNF.alpha. in the plasma supernatant is then determined by
ELISA.
[0126] In Vitro Test with PBMCs [0127] 1) The mononuclear cells
(PBMCS) from human potassium-EDTA whole blood, diluted 1:3, are
isolated by density gradient centrifugation
(Histopaque.RTM.-1.077). The cells are washed twice with DPBS
buffer, resuspended in macrophage SFM medium and adjusted to a cell
count of 1.times.10.sup.6 cells/ml. [0128] The resulting PBMCs
suspension (samples of in each case 390 .mu.l) and the test
substance are preincubated at 37.degree. C. in a CO.sub.2 incubator
(5% CO.sub.2; 95% moisture-saturated air) for 15 min. The samples
are then stimulated with in each case 1 .mu.l/ml of LPS (E. coli
026:B6) at 37.degree. C. in a CO.sub.2 incubator (5% CO.sub.2; 95%
moisture-saturated air) for 4 hours. The reaction is stopped by
placing the samples on ice, adding DPBS buffer and then
centrifuging at 15 880 g for 12 min. The amount of IL-1.beta. and
TNF.alpha. in the plasma supernatant is then determined by
ELISA.
[0129] 2) Kinase assay [0130] At 37.degree. C., microtiter plates
were coated for one hour with 50 .mu.l of ATF2 solution (20
.mu.g/ml). The plates were washed three times with water, and 50
.mu.l of kinase mixture (50 mM tris-HCl, 10 mM MgCl.sub.2, 10 mM
.beta.-glycerol phosphate, 10 .mu.g/ml of BSA, 1 mM DTT, 100 .mu.M
ATP, 100 .mu.M Na.sub.3VO.sub.4, 10 ng of activated p38a) with or
without inhibitor were added into the wells, and the plates were
incubated at 37.degree. C. for 1 hour. The plates were washed three
times and then incubated with phosphorus-ATF-2 antibody for one
hour. The plates were once more washed three times, and
goat-antirabbit IgG labeled with alkaline phosphatase was added at
37.degree. C. for one hour (to fix antibody-phosphorylated
protein/substrate complex). The plates were washed three times, and
the alkaline phosphatase/substrate solution (3 mM 4-NPP, 50 mM
NaHCO.sub.3, 50 mM MgCl.sub.2, 100 .mu.l/well) was added at
37.degree. C. for 1.5 hours. Formation of 4-nitrophenolate was
measured at 405 nm using a microtiter plate reader. The IC.sub.50
values were calculated.
[0131] The results of the in vitro tests are shown in table 1
below. TABLE-US-00001 TABLE 1 Test results Whole Compound IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) PBMCA K.sub.50 (.mu.M) blood No. p 38
TNF-.alpha. IL-1.beta. TNF-.alpha. IL-1.beta. 25.degree. 2.2 0.35
25b 3.8 2.8 0.30 25c 8.7 4.6 2.7 7.2 2.2 25d 1.9 0.15 25e 3.1 0.50
25f 0.65 0.63 0.108 25g 0.79 0.64 0.056 25h 0.83 0.67 0.085 17.3
22.3 25i 0.95 0.50 0.15 14.8 13.3 25j 0.70 0.72 0.23 25k 0.13 0.34
0.030 25l 0.24 0.35 0.031 14.9 17.1 25m 0.38 0.16 0.039 2.7 0.99
25n 0.34 0.17 0.041 25o 0.90 0.37 0.044 26a 60.0 1.8 26b 4.2 40.5
2.9 26c 1.42 3.2 0.20 26d 0.38 2.7 0.045 26e 21.0 0.18 27a 12.0 2.1
27b 9.3 6.9 2.45 27c 1.45 2.0 0.47 27d 0.27 0.91 0.040 10.0
15.7
[0132] The examples below illustrate the invention, without
limiting it.
EXAMPLE 1
a) 4-(4-Fluoroph nyl)-5-pyridin-4-yl-1,3-dihydroimidaz l
-2-thione
2-(4-Fluorophenyl)-3-hydroxy-3-pyridin-4-ylacrylonitrile (a1)
[0133] A mixture of ethyl isonicotinate (75.8 g; 0.5 mol) and
4-fluorophenylacetonitrile (67.6 g; 0.5 mol) was added dropwise to
a solution of metallic sodium (17.3 g; 0.7 mol) in absolute ethanol
(250 ml). The reaction mixture was stirred at 100.degree. C. for 15
min. The reaction mixture was then cooled in an ice bath, and 600
ml of distilled H.sub.2O were added. When the mixture was acidified
with concentrated HCl (90 ml), the hydrochloride of a1 was obtained
as yellow precipitate at pH 1. The precipitate was filtered off,
washed with H.sub.2O and dried under reduced pressure over
P.sub.2O.sub.5. M.p. 226.degree. C.
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone (a2)
[0134] A solution of a1 (40.6 g; 0.15 mol) in 48% strength
hydrobromic acid (130 ml) was stirred under reflux for 19 h. The
mixture was cooled in an ice bath, and the precipitate obtained
(4-fluorophenylacetic acid) was filtered off and washed with
H.sub.2O. When the filtrate was neutralized with ammonia water (80
ml) a2 was obtained as a dark-green precipitate which was filtered
off, washed with H.sub.2O and dried under reduced pressure over
P.sub.2O.sub.5: light-gray/beige powder. M.p. 215.degree. C.
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone oxime (a3)
[0135] Sodium acetate (36.1 g; 0.44 mol) and hydroxylamine
hydrochloride (22.0 g; 0.32 mol) were introduced into a suspension
of a2 (21.5 g; 0.1 mol) in 50% strength methanol (350 ml). The
reaction mixture was stirred under reflux for 1 h. When the clear
solution was cooled in an ice bath, a3 was obtained as a beige
precipitate which was filtered off, washed with H.sub.2O and dried
under reduced pressure over P.sub.2O.sub.5.
[0136] M.p. 155.degree. C.
2-(4-Fluorophenyl)-1-pyridin-4-ylethanone,
O-[(4-methylphenyl)sulfonyl]oxime (a4)
[0137] Under an atmosphere of argon, a3 (10.1 g; 0.04 mol) was
dissolved in absolute pyridine (50 ml). The solution was cooled to
6.degree. C., and toluenesulfonyl chloride (10.1 g; 0.05 mol) was
added a little at a time. After the addition had ended, the
reaction mixture was stirred at room temperature for 20 h. The
mixture was then poured into 500 ml of ice-water. The precipitate
(a4) was filtered off, washed with cold H.sub.2O and dried in a
drying cabinet at 50.degree. C. M.p. 201.degree. C.
4-(4-Fluorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione
(1a)
[0138] Under an atmosphere of argon, a solution of a4 (10.0 g; 0.03
mol) in absolute ethanol (56 ml) was cooled to 5.degree. C., and a
freshly prepared solution of metallic sodium (0.75 g; 0.03 mol) in
absolute ethanol (30 ml) was added dropwise. The reaction mixture
was stirred at 5.degree. C. for 5 h. After addition of diethyl
ether (500 ml), stirring was continued for 30 min. The precipitate
(TosOH) was filtered off and washed with diethyl ether (4.times.50
ml). The combined ethereal phase was extracted with 10% strength
hydrochloric acid (3.times.90 ml). The aqueous extract was
concentrated to a volume of about 40 ml, and potassium thiocyanate
(5.0 g; 0.05 mol) was added. The reaction mixture was stirred under
reflux for 1 h. When the mixture was neutralized with 5% strength
sodium bicarbonate solution (270 ml), a5 was obtained as a beige
precipitate which was filtered off, washed with H.sub.2O and dried
in a drying cabinet at 60.degree. C. Yield 5.6 g (79%); m.p.
382.degree. C.
[0139] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.1 (m, 2H,
4-F-Ph), 7.3 (m, 2H, 4-Pyr), 7.5 (m, 2H, 4-F-Ph), 8.5 (m, 2H,
4-Pyr), 12.7 (d, 2H, exchangeable, NH)
[0140] The following compounds were obtained in a corresponding
manner: [0141] 1b:
3-(4-fluorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione
[0142] 1c:
4-(4-chlorophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione
[0143] 1d:
4-(4-bromophenyl)-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione
[0144] 1e:
4-phenyl-5-pyridin-4-yl-1,3-dihydroimidazole-2-thione
EXAMPLE 2
1-Chloromethyl-4-methylsulfanylbenzene (2)
[0145] 4-Methylsulfanylbenzyl alcohol (30.5 g; 0.2 mol) was
dissolved in dichloromethane (180 ml). A solution of thionyl
chloride (23.8 g; 0.2 mol) in dichloromethane (120 ml) was added
dropwise to the initial charge, which was kept under reflux. The
reaction mixture was stirred under reflux for a further 2 h. The
solution was cooled to room temperature, washed with H.sub.2O
(2.times.250 ml), dried over Na.sub.2SO.sub.4 and concentrated. The
oily residue (6) was purified by column chromatography
(Al.sub.2O.sub.3, CH.sub.2Cl.sub.2).
[0146] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.46 (s, 3H,
CH.sub.3), 4.5 (s, 2H, CH.sub.2), 7.2-7.3 (q, 4H, 4-MeS-Ph)
EXAMPLE 3
1-Chloromethyl-4-methanesulfinylbenzene (3)
[0147] A solution of 2 (17.3 g; 0.1 mol) in glacial acetic acid
(150 ml) was cooled to 10.degree. C. A solution of H.sub.2O.sub.2
(35% strength solution; 13.1 g; 0.13 mol) in glacial acetic acid
(50 ml) was added dropwise to the initial charge. The reaction
mixture was stirred at room temperature for 2 h. The mixture was
cooled in an ice bath, ice (200 g) was added and the mixture was
neutralized with ammonia water (290 ml). The aqueous phase was
extracted with ethyl acetate (2.times.300 ml). The organic phase
was washed with H.sub.2O (2.times.300 ml), dried over
Na.sub.2SO.sub.4 and concentrated. By scratching and cooling the
oily residue, 3 was obtained in crystalline form.
[0148] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.73 (s, 3H,
CH.sub.3), 4.6 (s, 2H, CH.sub.2), 7.5 (d, 2H, 4-MeS(O)-Ph), 7.6 (d,
2H, 4-MeS(O)-Ph)
EXAMPLE 4
1-Chlormethyl-4-methanesulfonylbenzene (4)
[0149] m-Chloroperbenzoic acid (70%; 8.6 g; 0.04 mol) was
introduced into a solution of 3 (3.0 g; 0.02 mol) in chloroform (50
ml). The reaction mixture was stirred under reflux for 4 h. The
mixture was cooled to room temperature and filtered. The filtrate
was washed with saturated NaHCO.sub.3 solution (2.times.) and dried
over Na.sub.2SO.sub.4. After concentration of the organic phase, 8
remained as a crystalline white solid. M.p. 102.degree. C.
[0150] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 3.07 (s, 3H,
CH.sub.3), 4.6 (s, 2H, CH.sub.2), 7.6 (d, 2H, 4-MeSO.sub.2-Ph), 7.9
(d, 2H, 4-MeSO.sub.2-Ph)
EXAMPLE 5
Methyl 5-chlorosulfonyl-2-hydroxybenzoate (5a)
[0151] 5a was prepared from methyl salicylate (10.0 g; 65.7 mmol)
using the method described in the synthesis of 5c.
[0152] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 4.05 (s, 3H,
CH.sub.3), 7.18 (d, 1H, 8.9 Hz, C.sup.3--H), 8.09 (dd, 1H, 2.5/9.0
Hz, C.sup.4--H), 8.57 (d, 1H, 2.5 Hz, C.sup.6--H), 11.55 (s, 1H,
exchangeable, phenol-OH)
Methyl 5-chloro-3-chlorosulfonyl-2-hydroxybenzoate (5b)
[0153] 5b was prepared from methyl 5-chlorosalicylate (16.0 g; 85.7
mmol) using the method described in the synthesis of 5c.
[0154] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 4.06 (s, 3H,
CH.sub.3), 8.11 (d, 1H, 2.7 Hz, C.sup.6--H), 8.19 (d,1H, 2.7 Hz,
C.sup.4--H), 12.09 (s, 1H, exchangeable, phenol-OH)
Ethyl 3-chlorosulfnyl-4-methxybenzoate (5c)
[0155] A solution of ethyl 4-methoxybenzoate (15.7 g; 87.2 mmol) in
CCl.sub.4 (60 ml) was cooled to -15.degree. C., and chlorosulfonic
acid (17.5 ml; 263 mmol) was added dropwise over a period of 15
min, resulting in a temperature increase to -10.degree. C. After
the addition had ended, the reaction mixture was stirred at room
temperature for 2 h and then heated at 50.degree. C. until no more
starting material could be detected by thin-layer chromatography.
With ice-cooling and vigorous stirring, the reaction mixture was
added to a suspension of ice (50 g) in CCl.sub.4 (100 ml). The
mixture was stirred vigorously for 3 min. The organic phase was
separated off and the aqueous phase was extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml). The combined organic extracts
were washed with saturated NaCl solution (3.times.), dried over
Na.sub.2SO.sub.4 and concentrated. Trituration of the oily brown
residue with diethyl ether resulted in 5c precipitating as a
crystalline white solid.
[0156] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 1.41 (t, 3H, 7.1 Hz,
CH.sub.3), 4.14 (s, 3H, CH.sub.3), 4.42 (q, 2H, 7.1 Hz, CH.sub.2),
7.18 (d, 1H, 8.8 Hz, C.sup.5--H), 8.37 (dd, 1H, 2.1/8.8 Hz,
C.sup.6--H), 8.63 (d, 1H, 2.1 Hz, C.sup.2--H)
EXAMPLE 6
2-Hydroxy-5-mercaptobenzoic acid (6a)
[0157] 6a was prepared from 6a (0.50 g; 2.0 mmol) using the method
described in the synthesis of 7c, without alkylation with dimethyl
sulfate.
[0158] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 5.39 (bs, 1H,
exchangeable, carboxyl-OH), 6.90 (d, 1H, 8.7 Hz, C.sup.3--H), 7.45
(dd, 1H, 2.5/8.6 Hz, C.sup.4--H), 7.75 (d,1H, 2.5 Hz, C.sup.6--H),
phenol-OH not visible
EXAMPL 7
2-Hydroxy-5-methylsulfanylbenzoic acid (7a)
[0159] 7a was prepared from 5a (10.0 g; 40.0 mmol) using the method
described in the synthesis of 7c.
[0160] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.48 (s, 3H,
CH.sub.3), 6.97 (d, 1 H, 8.7 Hz, C.sup.3--H), 7.51 (dd, 1H, 2.5/8.7
Hz, C.sup.4--H), 6.97 (d, 1H, 8.7 Hz, C.sup.3--H), 7.87 (d, 1H, 2.4
Hz, C.sup.6--H), 10.26 (bs, 1H, phenol-OH), CO.sub.2H not
visible
5-Chloro-2-hydroxy-3-methylsulfanylbenzoic acid (7b)
[0161] 7b was prepared from 5b (13.0 g; 45.6 mmol) using the method
described in the synthesis of 7c.
[0162] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.47 (s, 3H,
CH.sub.3), 7.33 (d, 1H, 2.4 Hz, C.sup.6--H), 7.52 (d 1H, 2.4 Hz,
C.sup.4--H), phenol-OH and CO.sub.2H not visible
4-Methoxy-3-methylsulfanylbenzoic acid (7c)
[0163] Triphenylphosphine (20.5 g; 78.2 mmol) was introduced a
little at a time into a solution of 5c (5.1 g; 18.3 mmol) in
toluene (50 ml). The reaction mixture was stirred at room
temperature for 4.5 h. The precipitate (triphenylphosphine oxide)
was filtered off, and the yellow filtrate was extracted with 10%
strength aqueous sodium hydroxide solution (4.times.). Dimethyl
sulfate (2 ml) was added to the combined aqueous extract, and the
reaction mixture was stirred at room temperature for 2 h. The
precipitate obtained was dissolved by heating to reflux
temperature. The clear solution was cooled and adjusted to pH 1
using 20% strength hydrochloric acid. The precipitate (7c) was
filtered off, washed with H.sub.2O and dried under reduced pressure
over CaCl.sub.2.
[0164] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.43 (s, 3H,
S--CH.sub.3), 3.93 (s, 3H, O--CH.sub.3), 6.98 (d, 1H, 8.4 Hz,
C.sup.5--H), 7.79-7.86 (m, 2H, C.sup.2--/C.sup.6--H)
4-Hydroxy-3-methylsulfanylbnzoic acid (7d)
[0165] A suspension of 7c (0.5 g; 2.5 mmol) in glacial acetic
acid/48% strength hydrobromic acid (1+1, 7 ml) was stirred under
reflux for 6 h. The reaction mixture was cooled, added to H.sub.2O
(20 ml) and adjusted to pH 2 using 10% strength Na.sub.2CO.sub.3
solution. The aqueous solution was extracted with diethyl ether
(4.times.20 ml). The combined organic extract was washed with
saturated NaCl solution (2.times.), dried over Na.sub.2SO.sub.4 and
concentrated. On standing at room temperature, the off-brown oily
residue (7d) crystallized out. The crystals were triturated with
H.sub.2O, filtered off and dried.
[0166] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.38 (s, 3H,
CH.sub.3), 7.05 (d, 1 H, 8.5 Hz, C.sup.5--H), 8.02 (dd, 1H, 2.2/8.5
Hz, C.sup.6--H), 8.29 (d, 1H, 2.2 Hz, C.sup.2--H), phenol-OH and
CO.sub.2H not visible
EXAMPLE 8
2-Hydroxymethyl-4-methylsulfanylphenol (8a)
[0167] 8a was prepared from 7a (1.5 g; 8.1 mmol) using the method
described in the synthesis of 8c.
[0168] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.42 (s, 3H,
CH.sub.3), 4.79 (s, 2H, CH.sub.2), 6.81 (d, 1H, 8.4 Hz,
C.sup.6--H), 7.01 (d, 1H, 2.1 Hz, C.sup.3--H), 7.17 (dd, 1H,
2.3/8.4 Hz, C.sup.3--H), OH not visible
4-Chloro-2-hydroxymethyl-6-methylsulfanylphenol (8b)
[0169] 8b was prepared from 7b (2.2 g; 10.1 mmol) using the method
described in the synthesis of 8c.
[0170] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.38 (s, 3H,
CH.sub.3), 4.52 (s, 2H, CH.sub.2), 5.3-5.5 (bs, 1H, exchangeable,
hydroxyl-OH), 7.03 (d, 1H, 2.6 Hz, C.sup.5--H), 7.11 (d, 2.4 Hz,
C.sup.3--H), 9.02 (bs, 1H, exchangeable, phenol-OH)
4-Hydroxymthyl-2-methylsulfanylphenol (8c)
[0171] With ice-cooling, a solution of 7d (1.37 g; 7.4 mmol) in
abs. tetrahydrofuran (THF; 15 ml) was added to a suspension of 95%
pure LiAlH.sub.4 (0.55 g; 14 mmol) in absolute THF (10 ml) in a
three-necked flask (which had been dried by heating and flushed
with argon) such that there was only a moderate evolution of gas.
After the addition had ended, cooling was removed and the reaction
mixture was stirred at room temperature for 30 min and at
55-65.degree. C. for a further 21 h. With ice-cooling, ice-water
was added to the reaction mixture. The precipitate of Al(OH).sub.3
was dissolved by adding 10% strength sulfuric acid, and the
aqueous-acidic solution (pH 1) was extracted with diethyl ether
(3.times.50 ml). The combined ethereal extract was extracted with
10% strength aqueous sodium hydroxide solution (2.times.25 ml). The
combined sodium hydroxide solution was neutralized with 20%
strength hydrochloric acid. The precipitate (8c) was filtered off,
washed with H.sub.2O and dried. A further charge of 8c was obtained
by extraction of the neutral aqueous solution with diethyl ether.
The ethereal extract was washed with saturated NaCl solution, dried
over Na.sub.2SO.sub.4 and concentrated: crystalline white
solid.
[0172] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.34 (s, 3H,
CH.sub.3), 4.60 (s, 2H, CH.sub.2), 6.97 (d, 1H, 8.3 Hz,
C.sup.6--H), 7.24 (dd, 1H, 2.0/8.4 Hz, C.sup.5--H), 7.50 (d, 1H,
2.0 Hz, C.sup.3--H), OH not visible
EXAMPLE 9
2-Hydroxy-5-methylsulfanylbenzaldehyde (9a)
[0173] The title compound was obtained as a byproduct in the
synthesis of 8a.
[0174] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.48 (s, 3H,
CH.sub.3), 6.96 (d, 1H, 9.8 Hz, C.sup.3--H), 7.48-7.54 (m, 2H,
C.sup.4--/C.sup.6--H), 9.87 (s,1H, exchangeable, OH), 10.91 (s,1H,
aldehyde-H)
EXAMPL 10
4-(3-Chloroethyl)benznesulfonyl chloride (10a)
[0175] With ice-cooling, (2-chloroethyl)benzene (14.0 g; 0.1 mol)
was added dropwise over a period of 40 min to chlorosulfonic acid
(72 g). The brown solution was stirred at room temperature for 24
h, cooled in an ice-bath and, a little at a time, added to ice,
where a viscous material separated out that could not be filtered.
The aqueous solution was extracted with ethyl acetate (3.times.).
The combined organic extract was washed with 10% strength
NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4 and concentrated.
The oily residue was taken up in tert-butyl methyl ether/petroleum
ether. The solution was scratched with a glass rod and cooled. The
white crystals were filtered off and dried. Further reaction
product was obtained from the mother liquor. The crude product was
used without further purification for the synthesis of 11a.
[0176] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 3.20 (t, 2H, 6.8 Hz,
CH.sub.2), 3.79 (t, 2H, 6.8 Hz, CH.sub.2), 7.46-7.53 (m, 2H,
phenyl), 7.97-8.04 (m, 2H, phenyl)
4-(3-Chloropropyl)benzenesulfonyl chloride (10b)
[0177] 10b was prepared from (3-chloropropyl)benzene (15.5 g; 0.1
mol) using the method described in the synthesis of 10a. The crude
product was used without further purification for the synthesis of
11b.
[0178] MS: m/z (%) 253 (90. M.sup.+), 217 (100. M.sup.+-Cl), 189
(35), 153 (97, M.sup.+-SO.sub.2Cl), 125 (94), 119 (65,
phenylpropylcarbenium.sup.+), 91(90), 77 (29, phenyl.sup.+)
EXAMPLE 11
1-(3-Chloroethyl)-4-methylsulfanylbenzene (11a)
[0179] 11a was prepared from 10a (12.0 g; 0.05 mol) using the
method described in the synthesis of 11b.
[0180] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.47 (s, 3H,
CH.sub.3), 3.02 (t, 2H, 7.4 Hz, CH.sub.2), 3.68 (t, 2H, 7.5 Hz,
CH.sub.2), 7.11-7.25 (m, 4H, phenyl)
1-(3-Chloropropyl)-4-methylsulfanylbenzene (11b)
[0181] At room temperature, a solution of 10b (12.7 g; 5.0 mmol) in
diethyl ether (75 ml) was added dropwise over a period of 2.5 h to
a suspension of LiAlH.sub.4 (2.9 g; 7.6 mmol) in diethyl ether (50
ml). After the addition had ended, the reaction mixture was stirred
at room temperature and with occasional addition of LiAlH.sub.4
until no more starting material could be detected by thin-layer
chromatography (2.5 h). With ice-cooling, ice was introduced into
the reaction mixture, and the aqueous phase was acidified with 10%
hydrochloric acid (pH 1). The organic phase was removed and the
aqueous phase was extracted with diethyl ether (3.times.). The
combined organic extract was washed with 10% strength aqueous
sodium hydroxide solution (4.times.50 ml) until it was virtually
colorless. Dimethyl sulfate (9.0 g; 7.0 mmol) was added to the
combined sodium hydroxide extract, and the mixture was stirred at
room temperature for 16.5 h. The oily sediment was taken up in
diethyl ether. The organic phase was separated off and the aqueous
phase was again extracted with diethyl ether (2.times.). The
combined organic extract was dried over Na.sub.2SO.sub.4 and
concentrated. The brown oily residue was subjected to a kugelrohr
distillation (0.2 mbar, 250.degree. C.).
[0182] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.01-2.11 (m, 2H,
CH.sub.2), 2.46 (s, 3H, CH.sub.3), 2.73 (t, 2H, 7.1 Hz, CH.sub.2),
3.51 (t, 2H, 6.5 Hz, CH.sub.2), 7.09-7.25 (m, 4H, phenyl)
EXAMPLE 12
1-(2-Chloroethyl)-4-methanesulfinylbenzene (12a)
[0183] With cooling, a 35% strength solution of H.sub.2O.sub.2 (0.9
g; 9.3 mmol) was added to a solution of 11a (1.5 g; 8.0 mmol) in
glacial acetic acid (20 ml). After the addition had ended, the
reaction mixture was stirred at room temperature for 2.5 h diluted
with cooling with ice-water and adjusted to pH 8 using 25% strength
ammonia water. The oily white sediment was taken up in diethyl
ether and the aqueous phase was extracted with diethyl ether
(3.times.). The combined organic extract was dried over
Na.sub.2SO.sub.4 and concentrated.
[0184] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 2.73 (s, 3H,
CH.sub.3), 3.14 (t, 2H, 7.1 Hz, CH.sub.2), 3.76 (t, 2H, 7.1 Hz,
CH.sub.2), 7.38-7.42 (m, 2H, phenyl), 7.60-7.64 (m, 2H, phenyl)
1-(3-Chloropropyl)-4-methanesulfinylbenzene (12b)
[0185] 12b was prepared from 11b (2.0 g; 10.0 mmol) using the
method described in the synthesis of 12a. M.p.: 46.degree. C.
[0186] General methods for preparing the compounds of the formula
I:
Preparation of the 2-arylalkyl- or alkylsulfanylimidazoles (General
Method A)
[0187] A suspension of the respective imidazole-2-thione (1
equivalent), of the respective base (1.2 equivalents) and of the
respective arylalkyl or alkyl halide (1 equivalent) in ethanol/THF
(8+2) was stirred under reflux until no more imidazole-2-thione
could be detected by thin-layer chromatography. The reaction
mixture was cooled to room temperature and filtered. The filtrate,
which in most cases was of red/orange color, was concentrated, and
the residue was purified by column chromatography,
recrystallization or trituration. The compounds 13a-c, 14a-c and
17a-m were prepared in this manner.
Preparation of the 2-benzylsulfanylimidazoles Having phenolic
Functionality in the Radical R.sup.2 (General Method B)
[0188] By addition of 10% strength hydrochloric acid (10-15 drops),
the imidazole-2-thione 1a (1 equivalent) was dissolved in glacial
acetic acid (5 ml). The respective benzyl alcohol (1 equivalent)
was added to the initial charge, which had a light-yellow color,
and the reaction mixture was stirred at a suitable temperature
(temperature/time) until no more 1a could be detected by thin-layer
chromatography. In the case of the sulfoxides 18g-i, a 35% strength
solution of H.sub.2O.sub.2 was added, and the reaction mixture was
stirred at room temperature for a further 4 h. The reaction mixture
was diluted with H.sub.2O (5 ml) and adjusted to pH 8 using 25%
strength ammonia water. The precipitate was filtered off and washed
with water. The crude product was purified by column
chromatography, recrystallization or trituration. The
imidazol-2-ylsulfanylmethylphenols 18a-i were prepared in this
manner.
Preparation of N-substituted 2-aminopyridines (General Method
C)
[0189] Under argon, the respective 5-(2-halopyridin-4-yl)imidazole
(1 equivalent) was suspended in the respective amine (about 10
equivalents). The reaction mixture was stirred at the respective
temperature until no more starting material could be detected by
thin-layer chromatography. The reaction mixture was cooled to room
temperature and taken up in 10% citric acid which had been adjusted
beforehand to pH 5 using 20% strength NaOH. The aqueous emulsion
was extracted with ethyl acetate (3.times.). The combined organic
extract was washed with 10% strength citric acid/pH 5 (1.times.),
10% strength Na.sub.2CO.sub.3 solution (2.times.) and saturated
NaCl solution (1.times.), dried over Na.sub.2SO.sub.4 and
concentrated. The oily residue was separated by column
chromatography. The aminopyridines 25f-p, 26c-e and 27c-d were
prepared in this manner.
EXAMPLE 13
3-[5-(4-Fluorophenyl)-2-(4-methylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]-
-pyridine (13a)
[0190] Using the general method A, the title compound was obtained
from 1b (0.42 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a
reaction time of 4.5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0191] M.p. 163.degree. C.
[0192] IR (ATR) (attenuated total reflection) 1506, 1493, 1222
(C--F), 837, 806 cm.sup.-1
[0193] .sup.1H-NMR (DMSO-d.sub.6 ): .delta. (ppm) 2.45 (s, 3H,
CH.sub.3), 4.38 (s, 2H, CH.sub.2), 7.19-7.49 (m, 10H, 3-Pyr, 4-F-Ph
and 4-MeS-Ph), 7.78-7.82 (m, 1H, 3-Pyr), 8.45-8.47 (m, 1H, 3-Pyr),
8.61 (s, 1H, 3-Pyr), 12.71 (bs, 1H, exchangeable, NH)
3-[5-(4-Flurophnyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]--
pyridine (13b)
[0194] Using the general method A, the title compound was obtained
from 1b (0.42 g; 1.5 mmol) and 3 (0.27 g; 1.5 mmol) after a
reaction time of 8 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0195] M.p. 127.degree. C.
[0196] IR (ATR): 1506, 1222 (C--F), 1027 (S.dbd.O), 1013, 838, 811
cm.sup.-1
[0197] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.19 (s, 3H,
CH.sub.3), 4.46 (s, 2H, CH.sub.2), 7.16-7.46 (m, 5H, 3-Pyr and
4-F-Ph), 7.56-7.66 (m, 4H, 4-MeS(O)-Ph), 7.72-7.81 (m, 1H, 3-Pyr),
8.41-8.62 (m, 2H, 3-Pyr), 12.77 (bs, 1H, exchangeable, NH)
3-[5-(4-Fluorophenyl)-2-(4-methanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl-
]-pyridine (13c)
[0198] Using the general method A, the title compound was obtained
from 1b (0.42 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) and with
addition of Na.sub.2CO.sub.3 (0.43 g; 4.1 mmol) after a reaction
time of 6.5 hours and trituration with hot ethyl acetate. M.p.
129.degree. C.
[0199] IR (ATR): 1506, 1296 (SO2), 1222 (C--F), 1145 (SO2), 1089,
839, 812 cm.sup.-1
[0200] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.19 (s, 3H,
CH.sub.3), 4.50 (s, 2H, CH.sub.2), 7.17-7.45 (m, 5H, 3-Pyr and
4-F-Ph), 7.64-7.90 (m, 5H, 3-Pyr and 4-MeSO.sub.2-Ph), 8.43-8.61
(m, 2H, 3-Pyr), 12.78 (bs, 1H, exchangeable, NH)
EXAMPLE 14
4-[5-(4-Chlorophenyl)-2-(4-mthylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]--
pyridine (14a)
[0201] Using the general method A, the title compound was obtained
from 1c (0.26 g; 0.9 mmol) and 6 (0.15 g; 0.87 mmol) and with
addition of Na.sub.2CO.sub.3 (two spatula tips) after a reaction
time of 6.5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 236.degree. C.
[0202] IR (ATR): 1600, 1492, 1094, 1005, 968, 829, 684 (C--Cl), 561
cm.sup.-1
[0203] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.44 (s, 3H,
CH.sub.3), 4.38 (s, 2H, CH.sub.2), 7.18-7.56 (m, 10H, 4-Pyr,
4-Cl-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H, 4-Pyr), 12.86 (bs, 1H,
exchangeable, NH)
4-[5-(4-Chlorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl-
]-pyridine (14b)
[0204] Using the general method A, the title compound was obtained
from 1c (0.26 g; 0.9 mmol) and 3 (0.16 g; 0.85 mmol) and with
addition of a reaction time of 6.5 hours and separation by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p.
224.degree. C.
[0205] IR (ATR): 1600, 1510, 1490, 1033 (S.dbd.O), 1001, 967, 829,
677 cm.sup.-1 (C--Cl)
[0206] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.70 (s, 3H,
CH.sub.3), 4.47 (s, 2H, CH.sub.2), 7.31-7.65 (m, 10H, 4-Pyr,
4-Cl-Ph and 4-MeS(O)-Ph), 8.44-8.54 (m, 2H, 4-Pyr), 12.87 (bs, 1H,
exchangeable, NH)
4-[5-(4-Chlorphenyl)-2-(4-mthanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl]--
pyridin (14c)
[0207] Using the general method A, the title compound was obtained
from 1c (0.26 g; 0.9 mmol) and 4 (0.18 g; 0.9 mmol) and with
addition of Na.sub.2CO.sub.3 (two spatula tips) after a reaction
time of 6.5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 232.degree. C.
[0208] IR (ATR): 1603, 1490, 1300 (SO2), 1141 (SO2), 1086, 1002,
952, 829, 681 (C--Cl), 550 cm.sup.-1
[0209] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.19 (s, 3H,
CH.sub.3), 4.52 (s, 2H, CH.sub.2), 7.32-7.58 (m, 6H, 4-Pyr and
4-Cl-Ph), 7.67 (d, 2H, 8.2 Hz, 4-MeSO.sub.2-Ph), 7.88 (d, 2H, 8.3
Hz, 4-MeSO.sub.2-Ph, 8.45-8.55 (m, 2H, 4-Pyr), 12.89 (bs, 1H,
exchangeable, NH)
EXAMPLE 15
4-[5-(4-Bromophenyl)-2-(4-methylsulfanylbenzylsulfanyl)-3H-imidazol-4-yl]--
pyridine (15a)
[0210] Using the general method A, the title compound was obtained
from 1d (0.25 g; 0.75 mmol) and 2 (0.13 g; 0.72 mmol) after a
reaction time of 5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0211] IR (ATR): 1600, 1517, 1490, 1089, 1069, 1003, 968, 826
cm.sup.-1
[0212] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.43 (s, 3H,
CH.sub.3), 4.36 (s, 2H, CH.sub.2), 7.16-7.87 (m, 10H, 4-Pyr,
4-Br-Ph and 4-MeS-Ph), 8.45-8.55 (m, 2H, 4-Pyr), 12.90 (bs, 1H,
exchangeable, NH)
4-[5-(4-Bromophnyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazol-4-yl]--
pyridine (15b)
[0213] Using the general method A, the title compound was obtained
from 1d (0.25 g; 0.75 mmol) and 3 (0.14 g; 0.72 mmol) after a
reaction time of 10 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0214] M.p. 222.degree. C.
[0215] IR (ATR): 1604, 1487, 1035 (S.dbd.O), 1010, 1000, 966, 822
cm.sup.-1
[0216] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.71 (s, 3H,
CH.sub.3), 4.48 (s, 2H, CH.sub.2), 7.40-7.62 (m, 20H, 4-Pyr,
4-Br-Ph and 4-MeS(O)-Ph), 8.49-8.57 (m, 2H, 4-Pyr), 12.90 (bs, 1H,
exchangeable, NH)
4-[S-(4-Bromophenyl)-2-(4-methanesulfonylbenzylsulfanyl)-3H-imidazol-4-yl]-
-pyridine (15c)
[0217] Using the general method A, the title compound was obtained
from 1d (0.25 g; 0.75 mmol) and 4 (0.15 g; 0.72 mmol) after a
reaction time of 5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0218] M.p. 226.degree. C.
[0219] IR (ATR): 1605, 1318, 1303 (SO2), 1145 (SO2), 1003, 967,
957, 827, 822 cm.sup.-1
[0220] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.18 (s, 3H,
CH.sub.3), 4.50 (s, 2H, CH.sub.2), 7.33-7.89 (m, 10H, 4-Pyr,
4-Br-Ph and 4-MeSO.sub.2-Ph), 8.45-8.54 (m, 2H, 4-Pyr), 12.91 (bs,
1H, exchangeable, NH)
EXAMPL 16
4-[2-(4-Mthylsulfanylbenzylsulfanyl)-5-phenyl-3H-imidazl-4-yl]pyridine
(16a)
[0221] Using the general method A, the title compound was obtained
from 1e (0.38 g; 1.5 mmol) and 2 (0.25 g; 1.4 mmol) after a
reaction time of 5.75 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0222] M.p. 213.degree. C.
[0223] IR (ATR): 1601, 1491, 1417, 1094, 1004, 967, 828, 771, 700
cm.sup.-1
[0224] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.44 (s, 3H,
CH.sub.3), 4.38 (s, 2H, CH.sub.2), 7.18-7.58 (m, 11H 4-Pyr, Ph and
4-MeS-Ph), 8.44-8.47 (m, 2H, 4-Pyr), 12.82 (bs, 1H, exchangeable,
NH)
4-[2-(4-Methanesulfinylbenzylsulfanyl)-5-phenyl-3H-imidazol-4-yl]pyridine
(16b)
[0225] Using the general method A, the title compound was obtained
from 1e (0.38 g; 1.5 mmol) and 3 (0.27 g; 1.43 mmol) after a
reaction time of 5.5 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0226] M.p. 189.degree. C.
[0227] IR (ATR): 1603, 1494, 1051 (S.dbd.O), 1003, 833, 701
cm-1
[0228] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.71 (s, 3H,
CH.sub.3), 4.48 (s, 2H, CH.sub.2), 7.32-7.52 (m, 7H, 4-Pyr and Ph),
7.57-7.67 (m, 4H, 4-MeS(O)-Ph), 8.45-8.54 (m, 2H, 4-Pyr), 12.84
(bs, 1H, exchangeable, NH)
4-[2-(4-Methanesulfonylbenzylsulfanyl)-5-phenyl-3H-imidazol-4-yl]pyridine
(16c)
[0229] Using the general method A, the title compound was obtained
from 1e (0.38 g; 1.5 mmol) and 4 (0.29 g; 1.43 mmol) after a
reaction time of 4.25 hours and separation by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0230] M.p. 247.degree. C.
[0231] IR (ATR): 1602, 1298 (SO2), 1145 (SO2), 1006, 953, 827, 775,
701 cm.sup.-1
[0232] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.21 (s, 3H,
CH.sub.3), 4.54 (s, 2H, CH.sub.2), 7.31-7.58 (m, 7H, 4-Pyr and Ph),
7.70 (d, 2H, 8.3 Hz, 4-MeSO.sub.2-Ph), 7.91 (d, 2H, 8.3 Hz,
4-MeSO.sub.2-Ph), 8.45-8.59 (m, 2H, 4-Pyr), 12.87 (bs, 1H,
exchangeable, NH)
EXAMPLE 17
4{5-(4-Fluorophenyl)-2-[2-(4-methanesulfinylphenyl)ethylsulfanyl]-1H-imida-
zol-4-yl}pyridine (17a)
[0233] Using the general method A, the title compound was obtained
from 1a (0.25 g; 0.9 mmol) and 12a (0.22 g; 1.1 mmol) and with
addition of Na.sub.2CO.sub.3 (1 spatula tip) and a catalytic amount
of Nal after a reaction time of 50 hours and purification by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0234] M.p. 177.degree. C.
[0235] IR (ATR): 1221 (C--F), 1032 cm.sup.-1 (S.dbd.O)
[0236] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.71 (s, 3H,
CH.sub.3), 3.06-3.13 (m, 2H, CH.sub.2), 3.42-3.49 (m, 2H,
CH.sub.2), 7.25-7.65 (m, 1OH, 4-Pyr, 4-F-Ph and 4-MeS(O)-Ph),
8.40-8.58 (m, 2H, 4-Pyr), 12.80 (bs, 1H, exchangeable, NH)
4-{5-(4-Fluorophenyl)-2-[2-(4-methanesulfinylphenyl)propylsulfanyl]-1H-imi-
dazol-4-yl}pyridine (17b)
[0237] Using the general method A, the title compound was obtained
from 1a (0.25 g; 0.9 mmol) and 12b (0.22 g; 1.0 mmol) and with
addition of Na.sub.2CO.sub.3 (1 spatula tip) and a catalytic amount
of Nal after a reaction time of 40 hours and purification by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0238] M.p. 142.degree. C.
[0239] IR (ATR): 1222 (C--F), 1043 cm.sup.-1 (S.dbd.O)
[0240] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.95-2.09 (m, 2H,
CH.sub.2), 2.71 (s, 3H, CH.sub.3), 2.82 (t, 2H, 7.4 Hz, CH.sub.2),
3.15 (t, 2H, 7.0 Hz, CH.sub.2), 7.25-7.62 (m, 10H, 4-Pyr, 4-F-Ph
and 4-MeS(O)-Ph, 8.46-8.49 (m, 2H, 4-Pyr), 12.86 (bs, 1H,
exchangeable, NH)
4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]pyridine
(17c)
[0241] Using the general method A, the title compound was obtained
from 1a (0.28 g; 1.0 mmol) and 1-chloromethylbenzene (0.13 g; 1.0
mmol) after a reaction time of 6 hours and trituration with MeOH.
M.p. 223.degree. C.
[0242] IR (ATR): 1233 cm.sup.-1 (C--F)
[0243] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.41 (s, 2H,
CH.sub.2), 7.23-7.51 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8.44-8.47 (m,
2H, 4-Pyr), 12.82 (bs, 1H, exchangeable, NH)
4-[5-(4-Fluorophenyl)-2-phenethylsulfanyl-1
H-imidazol-4-yl]pyridine (17d)
[0244] Using the general method A, the title compound was obtained
from 1a (0.5 g; 1.9 mmol) and 2-chloroethylbenzene (0.28 g; 2.0
mmol) and with addition of Na.sub.2CO.sub.3 (1 spatula tip) and a
catalytic amount of Nal after a reaction time of 70 hours and
trituration with EtOH. M.p. 257.degree. C.
[0245] IR (ATR): 1223 cm.sup.-1 (C--F)
[0246] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.99 (t, 2H, 7.4
Hz, CH.sub.2), 3.40 (t, 2H, 7.5 Hz, CH.sub.2), 7.17-7.53 (m, 11H,
4-Pyr, 4-F-Ph and Bz), 8.44-8.46 (m, 2H, 4-Pyr), NH not visible
4-[5-(4-Fluorophenyl)-2-(3-phenylpropylsulfanyl)-1H-imidazol-4-yl]pyridine
(17e)
[0247] Using the general method A, the title compound was obtained
from 1a (0.5 g; 1.9 mmol) and 3-chloropropylbenzene (0.31 g; 2.0
mmol) and with addition of Na.sub.2CO.sub.3 (1 spatula tip) and a
catalytic amount of Nal after a reaction time of 70 hours and
trituration with EtOH. M.p. 183.degree. C.
[0248] IR (ATR): 1226 cm.sup.-1 (C--F)
[0249] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.90-2.04 (m, 2H,
CH.sub.2), 2.72 (t, 2H, 7.4 Hz, CH.sub.2), 3.12 (t, 2H, 7.0 Hz,
CH.sub.2), 7.18-7.51 (m, 11H, 4-Pyr, 4-F-Ph and Bz), 8.37-8.44 (m,
2H, 4-Pyr), 12.82 (bs, 1H, exchangeable, NH)
[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanyl]acetonitrile
(17f)
[0250] Using the general method A, the title compound was obtained
from 1a (1.1 g; 4.0 mmol) and chloroacetonitrile (0.30; 4.0 mmol)
after a reaction time of 18 hours and purification by column
chromatography (SiO.sub.2 60, ethyl acetate).
[0251] M.p. 219.degree. C.
[0252] IR (ATR): 2243 (CN), 1226 cm.sup.-1 (C--F)
[0253] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.32 (s, 2H,
CH.sub.2), 7.34-7.57 (m, 6H, 4-Pyr and 4-F-Ph), 8.50-8.52 (m, 2H,
4-Pyr), 13.20 (bs, 1H, exchangeable, NH)
4-[5-(4-Fluorophenyl)-2-(naphthalen-1-ylmethylsulfanyl)-1H-imidazol-4-yl]--
pyridine (17g)
[0254] Using the general method A, the title compound was obtained
from 1a (0.28 g; 1.0 mmol) and 1-chloromethylnaphthol (0.18 g; 1.0
mmol) after a reaction time of 6.5 hours and purification by column
chromatography (SiO.sub.2 60, ethyl acetate). M.p. 364.degree.
C.
[0255] IR (ATR): 1225 cm.sup.-1 (C--F)
[0256] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.90 (s, 2H,
CH.sub.2), 7.25-7.62 (m, 10H, 4-Pyr, 4-F-Ph and naphthyl),
7.80-7.98 (m, 2H, naphthyl), 8.20-8.23 (m, 1H, naphthyl), 8.48-8.52
(m, 2H, 4-Pyr), 12, (bs, 1H, exchangeable, NH)
4-[2-cyclohexylmethylsulfanyl-5-(4-fluorophenyl)-1H-imidazol-4-yl]pyridine
(17h)
[0257] Using the general method A, the title compound was obtained
from 1a (0.25 g; 0.9 mmol) and 1-chloromethylcyclohexane (0.18 g;
1.0 mmol) and with addition of Na.sub.2CO.sub.3 (1 spatula tip) and
a catalytic amount of Nal after a reaction time of 47 hours and
trituration with EtOH. M.p. 235.degree. C.
[0258] IR (ATR): 2922, 2852 (c-Hex), 1222 cm.sup.-1 (C--F)
[0259] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 0.95-1.23 (m, 5H,
cyc/o-Hex), 1.51-1.85 (m, 6H, cyclo-Hex), 3.06 (d, 2H, 6.7 Hz,
CH.sub.2), 7.22-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8.43-8.45 (m, 2H,
4-Pyr), 12.76 (bs, 1H, exchangeable, NH)
4-[5-(4-Fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridine
(17i)
[0260] Using the general method A, the title compound was obtained
from 1a (0.41 g; 1.5 mmol) and methyl iodide (0.27 g; 1.9 mmol)
after a reaction time of 8 hours and trituration with EtOH. M.p.
263.degree. C.
[0261] IR (ATR): 1226 cm.sup.-1 (C--F)
[0262] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.61 (s, 3H,
CH.sub.3), 7.22-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8.42-8.45 (m, 2H,
4-Pyr), NH not visible
4-[5-(4-Fluorophenyl)-2-(2-methylsulfanylbenzylsulfanyl)-1H-imidazol-4-yl]-
-pyridine (17j)
[0263] Using the general method A, the title compound was obtained
from 1a (0.28 g; 1.0 mmol) and
1-chloromethyl-2-methylsulfanylbenzene (0.17 g; 1.0 mmol) after a
reaction time of 5.5 hours and purification by column
chromatography (SiO.sub.2 60, ethyl acetate). M.p. 223.degree.
C.
[0264] IR (ATR): 1228 cm.sup.-1 (C--F)
[0265] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.51 (s, 3H,
CH.sub.3), 4.44 (s, 2H, CH.sub.2), 7.13-7.48 (m, 10H, 4-Pyr, 4-F-Ph
and 2-MeS-Ph), 8.43-8.46 (m, 2H, 4-Pyr)
4-[5-(4-Fluorophenyl)-2-(2-methanesulfinylbenzylsulfanyl)-1H-imidazol-4-yl-
]-pyridine (17k)
[0266] Using the general method A, the title compound was obtained
from 1a (0.28 g; 1.0 mmol) and
1-chloromethyl-2-methanesulfinylbenzene (0.18 g; 1.0 mmol) after a
reaction time of 4 hours and recrystallization from methanol/ethyl
acetate (1+1). M.p. 205.degree. C.
[0267] IR (KBr): 1213 (C--F), 1033 cm.sup.-1 (S.dbd.O)
[0268] .sup.1H-NMR (CD.sub.3PD): .delta. (ppm) 2.87 (s, 3H,
CH.sub.3), 4.50 (d, 1H, 13.6 Hz, CH.sub.2), 4.62 (d, 1H, 13.6 Hz,
CH.sub.2), 7.24-7.33 (m, 2H, 4-F-Ph), 7.47-7.62 (m, 5H, 4-F-Ph,
C.sup.4--/C.sup.5--/C.sup.6--H 2-MeS(O)-Ph), 7.95 (d,1 H, 7.2 Hz,
C.sup.3--H 2-MeS(O)-Ph), 7.99-8.03 (m, 2H, 4-Pyr), 8.55-8.58 (m,
2H, 4-Pyr)
4-[5-(4-Fluorophenyl)-2-(3-methylsulfanylbenzylsulfanyl)-1H-imidazol-4-yl]-
-pyridine (17l)
[0269] Using the general method A, the title compound was obtained
from 1a (1.1 g; 4.1 mmol) and
1-chloromethyl-3-methylsulfanylbenzene (0.7 g; 4.1 mmol) after a
reaction time of 11 hours and recrystallization from EtOH. M.p.
218.degree. C.
[0270] IR (KBr): 1225 cm.sup.-1 (C--F)
[0271] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.40 (s, 3H,
CH.sub.3), 4.46 (s, 2H, CH.sub.2), 7.16-7.43 (m, 6H, 4-F-Ph and
3-MeS-Ph), 7.56-7.63 (m, 2H, 4-F-Ph), 7.90-7.93 (m, 2H, 4-Pyr),
8.66-8.69 (m, 2H, 4-Pyr), NH not visible
4-[5-(4-Fluorophenyl)-2-(3-mthanesulfinylbenzylsulfanyl)-1H-imidazol-4-yl]-
-pyridine (17m)
[0272] A 35% strength solution of H.sub.2O.sub.2 (0.13 ml; 1.3
mmol) was added dropwise to a suspension of 17 l (0.50 g; 1.2 mmol)
in glacial acetic acid (7 ml). The reaction mixture was stirred at
room temperature for 20.5 h, diluted with H.sub.2O (5 ml), adjusted
to pH 9 using 25% strength ammonia water and extracted with ethyl
acetate (3.times.). The combined organic extract was washed with
saturated NaCl solution (3.times.) and dried over Na.sub.2SO.sub.4.
The oily crude product obtained after removal of the solvent was
triturated with diethyl ether/ethyl acetate (1+1) and the
semi-solid residue was purified by column chromatography (RP-18,
MeOH). M.p. 171.degree. C.
[0273] IR (KBr): 1228 (C--F), 1019 cm.sup.-1 (S.dbd.O)
[0274] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.67 (s, 3H,
CH.sub.3), 4.37 (s, 2H, CH.sub.2), 7.13-7.21 (m, 2H, 4-F-Ph),
7.37-7.58 (m, 8H, 4-Pyr, 4-F-Ph and 3-MeS(O)-Ph), 8.40-8.43 (m, 2H,
4-Pyr)
EXAMPLE 18
2-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenol
(18a)
[0275] Using the general method B (23 h, room temperature), the
title compound was obtained from 1a (0.20 g; 0.7 mmol) and
2-hydroxymethylphenol (0.10 g; 0.8 mmol) after trituration with
EtOH. M.p. 200.degree. C. (decomposition)
[0276] IR (ATR): 1266 (OH bending), 1222 (C--F), 1005 (C--O)
[0277] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.37 (s, 2H,
CH.sub.2), 6.70-6.85 (m, 2H, 2-HO-Ph), 7.05-7.14 (m, 1H, 2-HO-Ph),
7.23-7.53 (m, 7H, 4-Pyr, 4-F-Ph and 2-HO-Ph), 8.46-8.49 (m, 2H,
4-Pyr), 9.95 (bs, 1 H, exchangeable, OH), 12.81 (bs, 1H,
exchangeable, NH)
3-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenl
(18b)
[0278] Using the general method B (9 h, reflux), the title compound
was obtained from 1a (0.20 g; 0.7 mmol) and 3-hydroxymethylphenol
(0.10 g; 0.8 mmol) after purification by column chromatography
(SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
[0279] M.p. 230.degree. C.
[0280] IR (ATR): 1287 (OH bending), 1241 (C--F), 1007 cm.sup.-1
(C--O)
[0281] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.34 (s, 2H,
CH.sub.2), 6.65 (dd, 1H, 1.4/8.0 Hz, 3-HO-Ph C.sup.4--H), 6.79-6.82
(m, 2H, 3-HO-Ph C.sup.2--/C.sup.6--H), 7.07-7.15 (m, 1H, 3-HO-Ph
C.sup.5--H), 7.27-7.53 (m, 6H, 4-Pyr and 4-F-Ph), 9.45 (s, 1H,
exchangeable, OH), 12.83 (bs, 1H, exchangeable, NH)
4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]phenol
(18c)
[0282] Using the general method B (14 h, room temperature), the
title compound was obtained from 1a (0.20 g; 0.7 mmol) and
4-hydroxymethylphenol (0.10 g; 0.8 mmol) after purification by
column chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH
9+1).
[0283] M.p. 250.degree. C. (decomposition)
[0284] IR (ATR): 1271 (OH bending), 1232 (C--F), 1004 cm.sup.-1
(C--O)
[0285] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.32 (s, 2H,
CH.sub.2), 6.69 (d, 2H, 7.5 Hz, 4-HO-Ph), 7.19 (d, 2H, 7.9 Hz,
4-HO-Ph), 7.27-7.51 (m, 6H, 4-Pyr and 4-F-Ph), 8.43-8.53 (m, 2H,
4-Pyr), 9.41 (s, 1H, exchangeable, OH), 12.79 (bs, 1H,
exchangeable, NH)
2-[5-(4-Fluorphenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-4-meth-
ylsulfanylphenol (18d)
[0286] Using the general method B (1 h, room temperature), the
title compound was obtained from 1a (0.50 g; 2.9 mmol) and 8a (0.50
g; 2.9 mmol) after trituration with MeOH. M.p. 243.degree. C.
[0287] IR (KBr): 1275 (OH bending), 1230 (C--F), 1005 cm.sup.-1
(C--O)
[0288] .sup.1H-NMR (DMF-d.sub.7): .delta. (ppm) 2.36 (s, 3H,
CH.sub.3), 4.46 (s, 2H, CH.sub.2), 6.90 (d, 1H, 8.4 Hz, 2-HO-Ph
C.sup.3--H), 7.13 (dd, 1H, 2.3/8.3 Hz, 2-HO-Ph C.sup.4--H),
7.27-7.35 (m, 3H, 4-F-Ph and 2-HO-Ph C.sup.6--H), 7.51-7.53 (m, 2H,
4-Pyr), 7.58-7.65 (m, 2H, 4-F-Ph), 8.52-8.55 (m, 2H, 4-Pyr),
10.30-10.70 (bs, 1H, exchangeable, NH), OH not visible
4-Chloro-2-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmeth-
yl]-6-methylsulfanylphenol (18e)
[0289] Using the general method B (1.5 h, 75.degree. C.), the title
compound was obtained from 1a (0.80 g; 3.0 mmol) and 8b (0.60 g;
3.0 mmol) after trituration with MeOH. M.p. 220.degree. C.
(decomposition)
[0290] IR (KBr): 1259 (OH bending), 1225 (C--F), 1007 cm.sup.-1
(C--O)
[0291] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.34 (s, 3H,
CH.sub.3), 4.38 (s, 2H, CH.sub.2), 6.97 (d, 1H, 2.3 Hz, 3-Cl-Ph
C.sup.2--H), 7.17 (d, 1H, 2.3 Hz, 3-Cl-Ph C.sup.4--H), 7.23-7.51
(m, 6H, 4-Pyr and 4-F-Ph), 8.48-8.50 (m, 2H, 4-Pyr), 12.74 (bs, 1H,
exchangeable, NH), OH not visible
4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-2-met-
hylsulfanylphenol (18f)
[0292] Using the general method B (2 h, room temperature), the
title compound was obtained from 1a (0.20 g; 0.7 mmol) and 8c (0.14
g, 0.8 mmol) after trituration with MeOH. M.p. 230.degree. C.
(decomposition)
[0293] IR (KBr): 1227 (C--F), 1019 cm.sup.-1 (C--O)
[0294] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.21 (s, 3H,
CH.sub.3), 4.17 (s, 2H, CH.sub.2), 6.69 (d, 1H, 8.0 Hz, 4-HO-Ph
C.sup.3--H), 6.90-7.01 (m, 2H, 4-HO-Ph C.sup.2--/C.sup.6--H),
7.12-7.21 (m, 2H, 4-F-Ph), 7.32-7.53 (m, 4H, 4-Pyr and 4-F-Ph),
8.39-8.43 (m, 2H, 4-Pyr)
2-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-4-met-
hanesulfinylphenol (18g)
[0295] Using the general method B (1 h, room temperature), the
title compound was obtained from 1a (0.27 g; 1.0 mmol) and 8a (0.17
g; 1.0 mmol) with addition of 35% strength H.sub.2O.sub.2 solution
after recrystallization from toluene/THF (1+1). M.p. 216.degree.
C.
[0296] IR (KBr): 1278 (OH bending), 1232 (C--F), 1031 (S.dbd.O),
1003 cm.sup.-1 (C--O)
[0297] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.60 (s, 3H,
CH.sub.3), 4.33 (s, 2H, CH.sub.2), 6.96 (d, 1H, 8.2 Hz, 2-HO-Ph
C.sup.3--H), 7.11-7.21 (m, 2H, 4-F-Ph), 7.41-7.47 (m, 6H, 4-Pyr,
4-F-Ph and 2-HO-Ph C.sup.4--/C.sup.6--H), 8.39-8.42 (m, 2H,
4-Pyr)
4-Chloro-2-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmeth-
yl]-6-methanesulfinylphenol (18h)
[0298] Using the general method B (1.5 h, 75.degree. C.), the title
compound was obtained from 1a (0.27 g; 1.0 mmol) and 8b (0.21 g,
1.0 mmol) with addition of 35% strength H.sub.2O.sub.2 solution
after purification by column chromatography (SiO.sub.2 60,
acetone). M.p. 175.degree. C. (decomposition)
[0299] IR (KBr): 1265 (OH bending), 1236 (C--F), 1051 (S.dbd.O),
1005 cm.sup.-1 (C--O)
[0300] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.72 (s, 3H,
CH.sub.3), 4.39 (s, 2H, CH.sub.2), 7.14-7.23 (m, 2H, 4-F-Ph), 7.39
(d, 1H, 2.6 Hz, 3-Cl-Ph C.sup.2--H), 7.42-7.49 (m, 6H, 4-Pyr,
4-F-Ph and 3-Cl-Ph C.sup.4--H), 8.43-8.46 (m, 2H, 4-Pyr)
EXAMPL 19
4-[5-(4-Fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-ylsulfanylmethyl]-2-met-
hanesulfinylphenol (19)
[0301] Using the general method B (2.5 h, room temperature), the
title compound was obtained from 1a (0.20 g; 0.7 mmol) and 8c (0.14
g; 0.8 mmol) with addition of 35% strength H.sub.2O.sub.2 solution
after trituration with acetone.
[0302] M.p. 185.degree. C. (decomposition)
[0303] IR (KBr): 1296 (OH bending), 1230 (C--F), 1062 (S.dbd.O),
1013 cm.sup.-1 (C--O)
[0304] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.70 (s, 3H,
CH.sub.3), 4.28 (s, 2H, CH.sub.2), 6.78 (d, 1H, 8.3 Hz, 4-HO-Ph
C.sup.3--H), 7.12-7.21 (m, 2H, 4-F-Ph), 7.28 (dd, 1H, 2.2/8.3 Hz,
4-HO-Ph C.sup.2--H), 7.39-7.46 (m, 5H, 4-Pyr, 4-F-Ph and 4-HO-Ph
C.sup.6-H), 8.40 (m, 2H, 4-Pyr)
EXAMPLE 20
4-Fluoro-N-methoxy-N-methylbenzamide (20)
[0305] A suspension of 4-fluorobenzoic acid (20 g, 143 mmol) in
thionyl chloride (130 g; 1.1 mol) was stirred under reflux for 6 h:
vigorous evolution of gas, clear solution after about 10 min,
deepening of the color from yellow to orange. Excess thionyl
chloride was removed by distillation (initially atmospheric
pressure/40.degree. C., then membrane pump vacuum/40.degree. C.).
From the distillation residue, 4-fluorobenzoyl chloride was
distilled off under membrane pump vacuum at 90.degree. C. over a
short column. The reaction product crystallized on storing in a
fridge (n.sup.20.sub.D 1.5315; m.p. 9.degree. C., yield 20 g/89%).
Freshly distilled triethylamine (29 ml) was added to a suspension
of N,O-dimethylhydroxylamine hydrochloride (9.0 g; 92 mmol) in
CH.sub.2Cl.sub.2 (75 ml). The reaction mixture was stirred at room
temperature for 2 h and then cooled to -10.degree. C. With cooling,
4-fluorobenzoyl chloride (13.5 g; 85 mmol) was, over a period of 6
min, added dropwise to the initial charge. After the addition had
ended, cooling was removed and the reaction mixture was stirred at
room temperature for 1.5 h. The light-brown suspension was poured
into H.sub.2O (100 ml). The organic phase was removed and the
aqueous phase was extracted with diethyl ether (2.times.). The
combined extract was washed with saturated NaCl solution, dried
over NaSO.sub.4 and concentrated. The oily brown residue
crystallized on cooling and scratching. The crude product was dried
using an oil pump (residual triethylamine!) and reacted without
further purification.
[0306] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 3.37 (s, 3H,
NCH.sub.3), 3.54 (s, 3H, OCH.sub.3), 7.04-7.13 (m, 2H, 4-F-Ph),
7.71-7.78 (m, 2H, 4-F-Ph)
EXAMPLE 21
2-(2-Chloropyridin-4-yl)-1-(4-fluorophenyl)ethanone (21a)
[0307] n-BuLi (15% strength solution in n-hexane, 45 ml, 104 mmol)
was added dropwise to a solution, cooled to -85.degree. C., of
diisopropylamine (15 ml, 106 mmol) in abs. THF (150 ml) in a
double-necked flask which had been dried by heating and flushed
with argon: temperature increase to -50.degree. C. After the
addition had ended, the light-yellow solution was stirred at
-85.degree. C for 55 min. At -85.degree. C., a solution of
2-chloro-4-methylpyridine (2-chloro-.gamma.-picoline, 8.6 g; 68
mmol) in abs. THF (75 ml) was added dropwise to this initial
charge: temperature increase to -50.degree. C., initial change of
color to purple. After the addition had ended, the reaction mixture
was stirred at -85.degree. C. for 1 h, and a solution of 20 (12.4
g; 68 mmol) in abs. THF (75 ml) was added at this temperature over
a period of 3 min: temperature increase to -60.degree. C. The
purple slurry of the reaction mixture was stirred at -85.degree. C.
for 1 h and then, over a period of 1 h, warmed to 0.degree. C. The
mixture was poured into saturated NaCl solution (300 ml) which had
been covered with ethyl acetate (300 ml). The organic phase was
removed and the aqueous phase was extracted with ethyl acetate
(2.times.250 ml) and a little brown foamy precipitate of
1,3-bis-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)propan-2-ol
separated off at the interface. The combined organic extract was
washed with saturated NaCl solution, dried over NaSO.sub.4 and
concentrated. The oily residue was taken up in a little tert-butyl
methyl ether and stored at 4.degree. C. overnight. The crystals
were filtered off and dried.
[0308] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 4.26 (s, 2H,
CH.sub.2), 7.11-7.26 (m, 4H, C.sup.3--/C.sup.5--H 2-Cl-Pyr and
4-F-Ph), 7.99-8.06 (m, 2H, 4-F-Ph), 8.35 (dd, 1H, 0.6/5.1 Hz,
C.sup.6--H 2-Cl-Pyr)
1-(4-Fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (21b)
[0309] 21b was prepared from 2-fluoro-4-methylpyridine (13.9 g; 125
mmol) using the method described in the synthesis of 21a.
[0310] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 4.32 (s, 2H,
CH.sub.2), 6.85-6.86 (m, 1H, C.sup.3--H 2-F-Pyr), 7.08-7.19 (m, 3H,
C.sup.5--H 2-F-Pyr and 4-F-Ph), 8.00-8.07 (m, 2H, 4-F-Ph), 8.18 (d,
1H, 5.1 Hz, C.sup.6--H 2-F-Pyr)
2-(2-Bromopyridin-4-yl)-1-(4-fluorophenyl)ethanone (21c)
[0311] 21c was prepared from 2-bromo-4-methylpyridine (9.6 g; 56
mmol) using the method described in the synthesis of 21a.
[0312] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 4.35 (s, 2H,
CH.sub.2), 7.17-7.37 (m, 3H, 2-Br-Pyr and 4-F-Ph) 7.50 (s, 1H,
C.sup.3--H 2-Br-Pyr), 8.07-8.15 (m, 2H, 4-F-Ph), 8.42 (d, 1H, 5.1
Hz, C.sup.6--H 2-Br-Pyr)
EXAMPLE 22
1-(2-Chloropyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime
(22a)
[0313] With stirring and cooling in a water bath (about 10.degree.
C.), a solution of NaNO.sub.2 (0.85 g; 12.3 mmol) in H.sub.2O (10
ml) was added dropwise over a period of 2.5 min to a solution of
21a (3.0 g; 12 mmol) in glacial acetic acid. After the addition had
ended, the reaction mixture was stirred at room temperature for 0.5
h, H.sub.2O (60 ml) was added and stirring at room temperature was
continued for 3 h. The light-beige precipitate was filtered off,
washed with water and dried under reduced pressure over
CaCl.sub.2.
[0314] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.34-7.52 (m, 4H,
C.sup.3--/C.sup.5--H 2-Cl-Pyr and 4-F-Ph), 7.93-8.00 (m, 2H,
4-F-Ph), 8.47 (d, 1H, 5.2 Hz, C.sup.6--H 2-Cl-Pyr), 12.71 (bs, 1H,
exchangeable, OH)
1-(2-Fluoropyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime
(22b)
[0315] 22b was prepared from 21b (10.0 g; 43 mmol) using the method
described in the synthesis of 22a.
[0316] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.19-7.20 (m, 1H,
C.sup.3--H 2-F-Pyr), 7.35-7.47 (m, 3H, C.sup.5--H 2-F-Pyr and
4-F-Ph), 7.91-7.98 (m, 2H, 4-F-Ph), 8.29 (d, 1H, 5.3 Hz, C.sup.6--H
2-F-Pyr), 12.69 (s, 1H, exchangeable, OH)
1-(4-Fluorophenyl)-2-(2-isopropoxypyridin-4-yl)ethane-1,2-dione-2-oxime
(22c)
[0317] A solution of 22b (200 mg; 0.76 mmol) in HCl-saturated
isopropanol (15 ml) was stirred under reflux for 2.5 h. The
solution was concentrated and the yellowish-white residue was
triturated with a little ethanol, filtered off and dried.
[0318] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.24 (d, 6H, 6,2
Hz, 2.times.CH.sub.3), 5.15-5.27 (m, 1H,Me-thin-H), 6.54 (s, 1H,
C.sup.3--H 2-iso-O-Pyr), 7.08 (dd, 1H, 1,2/5.3 Hz, C.sup.5--H
2-iso-O-Pyr), 7.36-7.49 (m, 2H, 4-F-Ph), 7.88-7.97 (m, 2H, 4-F-Ph),
8.19 (d, 1H, 5.4 Hz, C.sup.6--H 2-iso-O-Pyr), 12.44 (bs, 1H,
exchangeable, OH)
1-(2-Bromopyridin-4-yl)-2-(4-fluorophenyl)ethane-1,2-dione-1-oxime
(22d)
[0319] 22d was prepared from 21c (5.0 g; 17 mmol) using the method
described in the synthesis of 22a.
[0320] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.40-7.48 (m, 3H,
C.sup.3--H 2-Br-Pyr and 4-F-Ph), 7.65 (d, 1H, 0.8 Hz, C.sup.5--H
2-Br-Pyr), 7.93-8.01 (m, 2H, 4-F-Ph), 8.45 (d, 1H, 5.2 Hz,
C.sup.6--H 2-Br-Pyr), 12.72 (bs, 1H, exchangeable, OH)
EXAMPLE 23
2-Amino-2-(2-chlropyridin-4-yl)-1-(4-fluorophenyl)ethanone
hydrochloride (23a)
[0321] With gentle heating, 22a (1.5 g; 5.4 mmol) was dissolved in
methanol (15 ml). The solution was cooled to room temperature,
HCl-containing methanol (20 ml) was added and the mixture was
transferred into a two-necked flask. Pd--C 10% (150 mg) was
introduced into the initial charge. The reaction vessel was
evacuated using an oil pump, and H.sub.2 was then introduced via a
gas inlet capillary (4.times.). At room temperature, the suspension
was shaken in a closed three-necked flask under an atmosphere of
H.sub.2 (240 strokes/min) until no more starting material could be
detected by thin-layer chromatography (6 h). The suspension was
filtered and the catalyst was washed with plenty of methanol. The
combined filtrate was concentrated and the mustard-colored
solid-amorphous residue was dried using an oil pump. The crude
product was used without further purification for the next reaction
step.
[0322] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 6.53 (bs, 1H,
methyne-H), 7.35-7.45 (m, 2H, 4-F-Ph), 7.59 (dd, 1H, 1.5/5.2 Hz,
C.sup.5--H 2-Cl-Pyr), 7.85 (d, 1H, 0.9 Hz,C.sup.3--H 2-Cl-Pyr),
8.17-8.25 (m, 2H, 4-F-Ph), 8.49 (d, 1H, 4.9 Hz, C.sup.6--H
2-Cl-Pyr), 9.33 (bs, 3H, exchangeable, NH.sub.3.sup.+)
2-Amino-2-(2-fluoropyridin-4-yl)-1-(4-fluorophenyl)ethanone
hydrochloride (23b)
[0323] With gentle heating, 22b (5.0 g; 19 mmol) was dissolved in
HCl-containing isopropanol (IsOH/HCl-saturated IsOH 1+1, 60 ml).
The yellowish solution was cooled to room temperature and
transferred into a two-necked flask (100 ml). Pd--C 10% (1.5 g) was
introduced into the initial charge. The reaction vessel was
evacuated using an oil pump and H.sub.2 was then introduced via a
gas inlet capillary (4.times.). At room temperature, the suspension
was shaken in a closed three-necked flask under an atmosphere of
H.sub.2 (240 strokes/min) until no more starting material could be
detected by thin-layer chromatography (6.5 h). The catalyst was
filtered off. The filtration residue was washed with plenty of
methanol (about 800 ml). The combined filtrates were concentrated
and the solid-amorphous residue was dried on an oil pump. The crude
product was used without further purification for the next reaction
step.
[0324] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 6.58 (bs, 1H,
methyne-H), 7.33-7.41 (m, 2H, 4-F-Ph), 7.54 (m, 2H,
C.sup.3--/C.sup.5--H 2-F-Pyr), 8.14-8.25 (m, 2H, 4-F-Ph), 8.30 (d,
1H, 5.5 Hz, C.sup.6--H 2-F-Pyr), 9.40 (bs, 3H, exchangeable,
NH.sub.3.sup.+)
2-Amino-1-(4-fluorophenyl)-2-(2-isopropoxypyridin-4-yl)ethanone
hydrochlorid (23c)
[0325] 23c was prepared from 22c (2.0 g; 7.6 mmol) using the method
described in the synthesis of 23a.
[0326] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.23 (d, 6H, 5.6
Hz, 2.times.CH.sub.3), 5.09-5.22 (m, 1H, methyne-H
CH(CH.sub.3).sub.2), 6.38-6.41 (bs, 1H, methyne-H
CH--NH.sub.3.sup.+), 7.00-7.08 (m, 2H, 2-iso-O-Pyr), 7.33-7.46 (m,
2H, 4-F-Ph), 8.14-8.23 (m, 3H, 2-iso-O-Pyr and 4-F-Ph), 9.21 (bs,
3H, exchangeable, NH.sub.3.sup.+)
2-Amino-1-(4-fluorophenyl)-2-(2-methoxypyridin-4-yl)ethanone
hydrochloride (23d)
[0327] 23d was formed by treating 22b (7.5 g; 29 mmol) under the
conditions described in the synthesis of 23a.
[0328] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.83 (s, 3H,
CH.sub.3), 6.44 (bs, 1H, methyne-H), 7.13-7.16 (m, 2H,
C.sup.3--/C.sup.5--H 2-MeO-Pyr), 7.34-7.46 (m, 2H, 4-F-Ph),
8.16-8.25 (m, 3H, C.sup.6--H 2-MeO-Pyr and 4-F-Ph), 9.29 (bs, 3H,
exchangeable, NH.sub.3.sup.+)
2-Amino-1-(4-fluorophenyl)-2-pyridin-4-ylethanone hydrochloride
(23e)
[0329] 23e was formed by treating 22c (4.0 g; 12.4 mmol) under the
conditions described in the synthesis of 23b.
[0330] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 6.78 (bs, 1H,
methyne-H), 7.32-7.38 (m, 2H, 4-F-Ph), 8.07-8.13 (m, 2H, 4-Pyr),
8.17-8.27 (m, 2H, 4-F-Ph), 8.92-8.95 (m, 2H, 4-Pyr), 9.43 (bs, 3H,
exchangeable, NH.sub.3.sup.+)
2-Amino-2-(2-bromopyridin-4-yl)-1-(4-fluorophenyl)ethanone
hydrochloride (23f)
[0331] A solution of 22d (1.8 g; 5.6 mmol) in absolute ethanol (30
ml) was cooled to -10.degree. C., and concentrated sulfuric acid
(1.3 ml) was added. With cooling, zinc dust (1.1 g) was added a
little at a time to the initial charge. The reaction mixture was
stirred at -10.degree. C. for 30 min and then warmed to room
temperature. The gray-green suspension was filtered and the white
residue (ZnSO.sub.4) was washed with plenty of ethanol. The
combined yellow filtrate was concentrated and the solid yellowish
residue was dried using an oil pump.
[0332] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 6.39 (bs, 1H,
methyne-H), 7.35-7.44 (m, 2H, 4-F-Ph), 7.56 (dd, 1H, 1.4/5.1 Hz,
C.sup.5--H 2-Br-Pyr), 7.91 (s, 1H, C.sup.3--H2-Br-Pyr), 8.12-8.19
(m, 2H, 4-F-Ph), 8.46 (d, 1H, 5.1 Hz, C.sup.6--H2-Br-Pyr), 8.94
(bs, 3H, exchangeable, NH.sub.3.sup.+)
EXAMPLE 24
4-(2-Chloropyridin-4-yl)-5-(4-fluorophenyl)-1,3-dihydroimidazole-2-thione
(24a)
[0333] With gentle heating, 23a (2.9 g; about 9.6 mmol) was
dissolved in absolute DMF (75 ml). Potassium thiocyanate (1.9 g;
19.6 mmol) was introduced into the clear orange-red solution:
immediate opalescence and a lighter color. The reaction mixture was
stirred under reflux for 1.5 h. The suspension was cooled to room
temperature and, with H.sub.2O cooling, diluted dropwise with
H.sub.2O (about 140 ml). The yellow precipitate was filtered off,
washed with H.sub.2O and dried under reduced pressure over
CaCl.sub.2.
[0334] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.12-7.52 (m, 6H,
C.sup.3--/C.sup.5--H 2-Cl-Pyr and 4-F-Ph), 8.27 (d, 1H, 5.2 Hz,
C.sup.6--H 2-Cl-Pyr), 12.82 (bs, 2H, exchangeable, 2.times.NH)
4-(4-Fluorophenyl)-5-(2-fluropyridin-4-yl)-1,3-dihydroimidazol-2-thione
(24b)
[0335] 24b was prepared from 23b (6.1 g; 20 mmol) using the method
described in the synthesis of 24a.
[0336] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 7.12-7.16 (m, 2H,
C.sup.3--/C.sup.5--H 2-F-Pyr), 7.28-7.27 (m, 2H, 4-F-Ph), 7.46-7.55
(m, 2H, 4-F-Ph), 8.13 (d, 1H, 5.1 Hz, C.sup.6--H 2-F-Pyr), 12.85
(bs, 2H, exchangeable, 2.times.NH)
4-(4-Fluorophenyl)-5-(2-isopropoxypyridin-4-yl)-1,3-dihydroimidazole-2-thi-
one (24c)
[0337] 24c was prepared from 23c (2.5 g; 7.6 mmol) using the method
described in the synthesis of 24a.
[0338] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.24 (d, 6H, 6,2
Hz, 2.times.CH.sub.3), 5.10-5.19 (m, 1H, methyne-H), 6.69-6.76 (m,
2H, 2-iso-O-Pyr), 7.24-7.32 (m, 2H, 4-F-Ph), 7.42-7.49 (m, 2H,
4-F-Ph), 8.02 (d, 1H, 5.5 Hz, C.sup.6--H 2-iso-O-Pyr), 12.68 (bs,
2H, exchangeable, 2 .times.NH)
4-(4-Fluorophenyl)-5-(2-methoxypyridin-4-yl)-1,3-dihydroimidazole-2-thione
(24d)
[0339] Potassium thiocyanate (2 g, 20.6 mmol) was introduced into a
solution of 23d (3.2 g; 10.8 mmol) in 10% strength hydrochloric
acid (50 ml). The reaction mixture was stirred under reflux for 30
min. The orange solution was cooled and neutralized using 10%
strength NaHCO.sub.3 solution. The precipitate was filtered off,
washed with H.sub.2O and dried under reduced pressure over
CaCl.sub.2. The crude product was triturated with ethanol, and
insoluble components were filtered off. On standing, 24d
precipitated from the ethanolic filtrate.
[0340] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 3.81 (s, 3H,
OCH.sub.3), 6,79-6.82 (m, 2H, C.sup.3--/C.sup.5--H2-MeO-Pyr),
7.26-7.50 (m, 4H, 4-F-Ph), 8.06 (d, 1H, 5.3 Hz, C.sup.6--H
2-MeO-Pyr), 12.65 (bs, 2H, exchangeable, 2.times.NH)
EXAMPL 25
2-Chloro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine
(25a)
[0341] Using the general method A, the title compound was obtained
from 24a (0.5 g; 1.6 mmol) and methyl iodide (0.35 g; 2.5 mmol)
after a reaction time of 12 hours and purification by column
chromatography (Al.sub.2O.sub.3, CH.sub.2Cl.sub.2/ethyl acetate
1+1). M.p. 236.degree. C.
[0342] IR (ATR): 3126, 3057, 2929, 1591, 1529, 1499, 1389, 1231
(C--F), 1159, 996, 976, 844, 780 cm.sup.-1
[0343] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.62 (s, 1H,
CH.sub.3), 7.27-7.36 (m, 3H, 2-Cl-Pyr and 4-F-Ph), 7.45-7.55 (m,
3H, 2-Cl-Pyr and 4-F-Ph), 8.24 (d, 1H, 5.1 Hz, C.sup.6--H
2-Cl-Pyr), 12.85 (bs, 1H, exchangeable, NH)
2-Fluoro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridine
(25b)
[0344] Using the general method A, the title compound was obtained
from 24b (0.95 g; 3.3 mmol) and methyl iodide (1.4 g; 9.9 mmol)
after a reaction time of 40 hours. The crude product was boiled
with CH.sub.2Cl.sub.2/ethyl acetate (1+1). The combined organic
extract was decolorized using Al.sub.2O.sub.3, and the residue
obtained after concentration of the filtrate was triturated with a
little EtOH. M.p. 224.degree. C.
[0345] IR (ATR): 3073, 1609, 1497, 1421, 1234, 1219 (C--F), 1159,
1002, 883, 851, 833, 815 cm.sup.-1
[0346] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.62 (s, 3H,
CH.sub.3), 7.08 (s, 1H, C.sup.3--H 2-F-Pyr), 7.26-7.35 (m, 3H,
C.sup.5--H 2-F-Pyr and 4-F-Ph), 7.46-7.54 (m, 2H, 4-F-Ph), 8.08 (d,
1H, 5.3 Hz, C.sup.6--H 2-F-Pyr), 12.85 (bs, 1H, exchangeable,
NH)
4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-isopropoxypyrid-
in (25c)
[0347] NaH (55-65%; 1.0 g; about 23 mmol) was introduced into a
solution of 24c (4.0 g; 13.8 mmol) in absolute THF (60 ml). This
initial charge was stirred at room temperature for 5 min, and a
solution of methyl iodide (2.2 g; 17.3 mmol) in absolute THF (5 ml)
was added dropwise with H.sub.2O cooling. The reaction mixture was
stirred at room temperature for 1 h. The clear brown solution was
concentrated and the residue was taken up in H.sub.2O. The aqueous
solution was neutralized using 10% strength hydrochloric acid and
extracted with ethyl acetate (2.times.). The combined organic
extract was washed with saturated NaCl solution, dried over
Na.sub.2SO.sub.4 and concentrated. The semi-solid residue was
extracted by boiling with tert-butyl methyl ether (2.times.) and
filtered. The clear ethereal filtrate was concentrated and the
solid residue was triturated with a little tert-butyl methyl ether,
filtered off and dried. Further reaction product was obtained by
column chromatographic separation of the mother liquor (SiO.sub.2
60, CH.sub.2Cl.sub.2/ethyl acetate 1+1). M.p. 141.degree. C.
[0348] IR (ATR): 2928, 1610, 1544, 1509, 1412, 1314, 1222 (C--F),
1104, 1005, 954, 865, 843, 816 cm.sup.-1
[0349] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 1.28 (d, 6H, 6.1 Hz,
2.times.CH.sub.3), 2.63 (s, 3H, SCH.sub.3), 5.08-5.14 (m, 1H,
methyne-H), 6.76 (s, 1H, C.sup.3--H 2-iso-O-Pyr), 6.88 (dd, 1H,
1.4/5.4 Hz, C.sup.5--H 2-iso-O-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph),
7.40-7.47 (m, 2H, 4-F-Ph), 7.95 (dd, 1H, 0.7/5.4 Hz, C.sup.6--H
2-iso-O-Pyr)
4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-2-methoxypyridine
(25d)
[0350] A solution of 24d (1.0 g; 3.3 mmol) and methyl iodide (5.6
g; 39 mmol) in methanol (50 ml) was stirred under reflux for 3 h.
The reaction mixture was cooled and filtered. The filtrate was
concentrated and the residue was taken up in ethanol. Insoluble
components were filtered off and the filtrate was concentrated. The
residue was taken up in CH.sub.2Cl.sub.2/EtOH (9+1). Insoluble
components were filtered off, and the filtrate was separated by
column chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1).
M.p. 158.degree. C.
[0351] IR (ATR): 1618, 1608, 1497, 1391, 1222 (C--F), 1212, 1036,
835, 825 cm.sup.-1
[0352] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.67 (s, 3H,
SCH.sub.3), 3.90 (s, 3H, OCH.sub.3), 6.87-6.89 (m, 1H, C.sup.3--H
2-MeO-Pyr), 6.98 (dd, 1H, 1.5/5.5 Hz, C.sup.5-H2-MeO-Pyr),
7.16-7.24 (m, 2H, 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph), 8.03 (dd, 1H,
0.7/5.5 Hz, C.sup.6--H 2-MeO-Pyr)
4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]-1H-pyridin-2-one
(25e)
[0353] When 23d (8.8 g; 31 mmol) was treated with potassium
thiocyanate in boiling DMF analogously to the method described for
24a, the only reaction product obtained was 25e. M.p. 314.degree.
C. (decomposition). After cyclization, giving the
1,3-dihydroimidazolethione, the methyl group from the methoxy
substituent is transferred to the nucleophilic sulfur atom of the
thione, with formation firstly of the 2-methylsulfanyl-3H-imidazole
and, secondly, the 2-hydroxypyridine/1H-pyridin-2-one.
[0354] IR (ATR): 1634 (pyridone I), 1610, 1557 (pyridone II), 1493,
1220 (C--F), 968, 837, 800 cm.sup.-1
[0355] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.61 (s, 3H,
SCH.sub.3), 6.16 (bs, 1H, C.sup.3--H pyridone), 6.34 (s, 1H,
C.sup.5--H pyridone), 7.25-7.33 (m, 3H, C.sup.6--H pyridone and
4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph), 11.38 (bs, 1H, exchangeable,
pyridone-NH), 12.71 (bs, 1H, exchangeable, imidazole-NH)
Benzyl{4-[S-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-y-
l)-amine (25f)
[0356] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and benzylamine (0.8 g; 7.5 mmol) after
a reaction time of 5 hours at 160.degree. C. and separation by
column chromatography (Al.sub.2O.sub.3, CH.sub.2Cl.sub.2/ethyl
acetate 1+1).
[0357] M.p. 152.degree. C. (decomposition)
[0358] IR (ATR): 3234 (NH), 3006, 2916, 1601, 1583, 1501, 1451,
1432, 1353, 1225 (C--F), 1074, 844, 813, 729, 695 cm.sup.-1
[0359] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.59 (s, 3H,
CH.sub.3), 4.37 (s, 2H, CH.sub.2), 6.56-6.59 (m, 2H,
C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.04-7.44 (m, 9H, Ph and
4-F-Ph), 7.83 (d, 1H, 5.6 Hz, C.sup.6--H 2-amino-Pyr)
{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(4--
methoxybenzyl)amine (25g)
[0360] Using the general method C, the title compound was obtained
from 25b (0.44 g; 1.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6
mmol) after a reaction time of 7 hours at 160.degree. C. and
separation by column chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/EtOH 9+1).
[0361] M.p. 207.degree. C.
[0362] IR (ATR): 1598, 1558,1510, 1244, 1217 (C--F), 846, 812
cm.sup.-1
[0363] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.61 (s, 3H,
SCH.sub.3), 3.75 (s, 3H, OCH.sub.3), 4.30 (s, 2H, CH.sub.2),
6.56-6.59 (m, 2H, C.sup.3--/C.sup.5--H 2-amino-Pyr), 6.81-7.30 (m,
6H, 4-MeO-Ph and 4-F-Ph), 7.39-7.46 (m, 2H, 4-F-Ph), 7.84 (d, 1H,
6.0 Hz, C.sup.6--H 2-amino-Pyr)
{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-(4--
methylbenzyl)amine (25h)
[0364] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and 4-methylbenzylamine (0.85 g; 7.0
mmol) after a reaction time of 6 hours at 160.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9+1). M.p.185.degree. C.
[0365] IR (ATR): 1600, 1559, 1502, 1427, 1218 (C--F), 844, 809
cm.sup.-1
[0366] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.29 (s, 3H, CH3),
2.60 (s, 3H, SCH3), 4.32 (s, 2H, CH2), 6.57-6.60 (m, 2H, C3-/C5-H
2-amino-Pyr), 7.05-7.50 (m, 8H, 4-Me-Ph and 4-F-Ph), 7.83 (d, 1H,
5.3 Hz, C6-H2-amino-Pyr)
(4-Chlorobenzyl)-{4-[5-(4-flurophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]--
pyridin-2-yl}amine (25i)
[0367] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and 4-chlorobenzylamine (1.0 g; 7.0
mmol) after a reaction time of 5.5 hours under reflux and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 195.degree. C.
[0368] IR (ATR): 3409, 1597, 1549, 1502, 1489, 1422, 1218 (C--F),
843, 814, 793 cm.sup.-1
[0369] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.60 (s, 3H,
SCH.sub.3), 4.38 (s, 2H, CH.sub.2), 6.57-6.60 (m, 2H,
C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.05-7.14 (m, 2H, 4-F-Ph),
7.22-7.30 (m, 4H, 4-Cl-Ph), 7.38-7.45 (m, 2H, 4-F-Ph), 7.83 (d, 1H,
5.7 Hz, C.sup.6--H 2-amino-Pyr)
(3,4-Dichlorobenzyl)-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol4--
yl]-pyridin-2-yl}amine (25j)
[0370] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and 3,4-dichlorobenzylamine (1.2 g; 6.8
mmol) after a reaction time of 7.5 hours at 160.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 212.degree. C.
[0371] IR (ATR): 3409, 1600, 1552, 1509, 1490, 1424, 1225 (C--F),
842, 827, 813 cm.sup.-1
[0372] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.60 (s, 3H,
SCH.sub.3), 4.39 (s, 2H, CH.sub.2), 6.56-6.62 (m, 2H,
C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.06-7.50 (m, 7H, 3,4-di-Cl-Ph
and 4-F-Ph), 7.84 (d, 1H, 5.5 Hz, C.sup.6--H 2-amino-Pyr)
{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazl-4-yl]pyridin-2-yl}-phen-
ylamine (25k)
[0373] Using the general method C, the title compound was prepared
from 25b (0.2 g; 0.7 mmol) and aniline (0.65 g; 7.0 mmol) after a
reaction time of 6 hours under reflux and separation by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p.
228.degree. C.
[0374] IR (ATR): 3031, 1610, 1590, 1561, 1504, 1433, 1265, 1225
(C--F), 839, 827, 749, 695 cm.sup.-1
[0375] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.62 (s, 3H,
CH.sub.3), 5.95-6.13 (m, 2H, C.sup.3--/C.sup.5--H2-Pyr), 6.68-7.60
(m, 9H, Ph and 4-F-Ph), 7.97-8.01 (m, 1H, C.sup.6--H 2-Amino-Pyr),
8.99 (bs, 1H, exchangeable, anilino-NH), 12.68 (bs, 1H,
exchangeable, imidazole-NH)
{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol4-yl]pyridin-2-yl}-phen-
ethylamine (25l)
[0376] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and 2-phenylethylamine (0.85 g; 7.0
mmol) after a reaction time of 5.5 hours at 160.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 99.degree. C.
[0377] IR (ATR): 3409, 1604, 1546, 1504, 1220 (C--F), 838, 813, 698
cm.sup.-1
[0378] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.61 (s, 3H,
SCH.sub.3), 2.81 (t, 2H, 7.7 Hz, NCH.sub.2), 3.41 (t, 2H, 7.7 Hz,
CH.sub.2Ph), 6.55-6.57 (m, 2H, C.sup.3--/C.sup.5--H 2-amino-Pyr),
7.08-7.26 (m, 7H, Ph and 4-F-Ph), 7.42-7.49 (m, 2H, 4-F-Ph), 7.82
(d, 1H, 6.1 Hz, C.sup.6--H 2-amino-Pyr)
(RS)-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl-
}-(1-phenylethyl)amine (25m)
[0379] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and (RS)-1-phenylethylamine (0.80 g; 6.6
mmol) after a reaction time of 7 hours at 160.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 117-119.degree. C.
[0380] IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C--F), 1157,
838, 814, 699 cm.sup.-1
[0381] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 1.37 (d, 3H, 5.5
Hz, CH.sub.3), 2.58 (s, 3H, SCH.sub.3), 4.82-5.03 (m, 1H,
methyne-H), 6.39-7.74 (m, 12H, Ph, 2-amino-Pyr and 4-F-Ph), 12.57
(bs, 1H, exchangeable, NH)
(R)-{4-[5-(4-Fluorophenyl)-2-methylsuIfanyl-3H-imidazol-4-yl]pyridin-2-yl}-
-(1-phenylethyl)amine (25n)
[0382] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and (R)-1-phenylethylamine (0.80 g; 6.6
mmol) after a reaction time of 7 hours at 170.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/ethyl acetate 1+1). M.p. 117-119.degree. C.
[0383] IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C--F), 1157,
838, 814, 699 cm.sup.-1
[0384] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 1.44 (d, 3H, 6.9 Hz,
CH.sub.3), 2.59 (s, 3H, SCH.sub.3), 4.62-4.69 (m, 1H, methyne-H),
6.47-6.57 (m, 2H, C.sup.3--/C.sup.5--H2-amino-Pyr), 7.05-7.42 (m,
9H, Ph and 4-F-Ph), 7.80 (d, 1 H, 5.5 Hz, C.sup.6--H
2-amino-Pyr)
(S)-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-
-(1-phenylethyl)amine (25o)
[0385] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and (S)-1-phenylethylamine (0.80 g; 6.6
mmol) after a reaction time of 13 hours at 170.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/ethyl acetate 1+1). M.p. 117-119.degree. C.
[0386] IR (ATR): 2926, 1607, 1547, 1502, 1434, 1221 (C--F), 1157,
838, 814, 699 cm.sup.-1
[0387] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 1.44 (d, 3H, 6.9 Hz,
CH.sub.3), 2.59 (s, 3H, SCH.sub.3), 4.62-4.69 (m, 1H, methyne-H),
6.47-6.57 (m, 2H, C.sup.3--/C.sup.5--H2-amino-Pyr), 7.05-7.42 (m,
9H, Ph and 4-F-Ph), 7.80 (dd, 1H, 0.5/5.5 Hz, C.sup.6--H
2-amino-Pyr)
Benzyl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2--
yl}-methylamine (25p)
[0388] Using the general method C, the title compound was obtained
from 25b (0.2 g; 0.7 mmol) and N-methylbenzylamine (0.85 g; 7.0
mmol) after a reaction time of 7 hours at 180.degree. C. and two
column-chromatographic separations (SiO.sub.2 60,
CH.sub.2Cl.sub.2/ethyl acetate 1+1). M.p. 79.degree. C.
[0389] IR (ATR): 2924, 1601, 1494, 1407, 1219 (C--F), 837, 810,
730, 696 cm.sup.-1
[0390] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.60 (s, 3H,
SCH.sub.3), 2.97 (s, 3H, NCH.sub.3), 4.64 (s, 2H, CH.sub.2)
6.64-6.66 (m, 2H, C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.02-7.45 (m,
9H, Ph and 4-F-Ph), 7.96 (d, 1H, 5.0 Hz, C.sup.6--H
2-amino-Pyr)
[0391] The compounds compiled in Table 2 below were obtained using
the above method: TABLE-US-00002 TABLE 2 Ex. Method Name Structure
25q C (4-Fluorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR29## 25r C
(4-Chlorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR30## 25s C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-m-tolylamine ##STR31## 25t C
(2,4-Difluorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR32## 25u C
(2,6-Dichlorophenyl)-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR33## 25v C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
pyridin-2-yl}-(1-phenylpropyl)amine ##STR34## 25w C
3,3-Diphenylpropyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR35## 25x C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
pyridin-2-yl}naphthalen-1-yl- methylamine ##STR36## 25y C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
pyridin-2-yl}naphthalen-2-yl- methylamine ##STR37##
EXAMPLE 26
4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-chloropyridine
(26a)
[0392] Using the general method A, the title compound was obtained
from 24a (0.3 g; 1.0 mmol) and benzyl chloride (0.12 g; 1.0 mmol)
after a reaction time of 6 hours and purification by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p.
223.degree. C.
[0393] IR (ATR): 2939, 1591, 1530, 1505, 1233 (C--F), 997, 838,
782, 700 cm.sup.-1
[0394] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.43 (s, 2H,
CH.sub.2), 7.27-7.47 (m, 11H, 2-Cl-Pyr, Ph and 4-F-Ph), 8.26 (d,
1H, 5.2 Hz, C.sup.6--H 2-Cl-Pyr), 12.94 (bs, 1H, exchangeable,
NH)
4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-fluoropyridine
(26b)
[0395] Using the general method A, the title compound was obtained
from 24b (5.1 g; 17.6 mmol) and benzyl bromide (9.2 g; 54 mmol)
after a reaction time of 1.5 hours and separation by column
chromatography (Al.sub.2O.sub.3, CH.sub.2Cl.sub.2/ethyl acetate
1+1). M.p. 174.degree. C.
[0396] IR (ATR): 3028, 2948, 1611, 1496, 1413, 1228 (C--F), 1203,
1003, 879, 838, 698 cm.sup.-1
[0397] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.43 (s, 2H,
CH.sub.2), 7.11 (s, 1H, C.sup.3--H 2-F-Pyr), 7.25-7.51 (m, 10H,
C.sup.5--H 2-F-Pyr, Ph and 4-F-Ph), 8.10 (d, 1H, 5.3 Hz, C.sup.6--H
2-F-Pyr), 12.93 (bs, 1H, exchangeable, NH)
Benzyl-{4-[2-benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2--
yl}-amine (26c)
[0398] Using the general method C, the title compound was obtained
from 26b (0.2 g; 0.53 mmol) and benzylamine (0.60 g; 5.6 mmol)
after a reaction time of 6 hours at 180.degree. C. and separation
by column chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/ethyl
acetate 1+1). M.p. 185.degree. C.
[0399] IR (ATR): 3407 (NH), 3025, 2855, 2713, 1599, 1550, 1489,
1356, 1220 (C--F), 1155, 840, 814, 693 cm.sup.-1
[0400] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 4.21 (s, 2H,
NCH.sub.2), 4.38 (s, 2H, SCH.sub.2), 6.52-6.55 (m,
C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.03-7.38 (m, 9H, Ph and
4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C.sup.6--H 2-amino-Pyr)
(RS)-}4-[2-Benzylsulfanyl-S-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2-yl-
}-(1-phenylethyl)amine (26d)
[0401] Using the general method C, the title compound was obtained
from 26b (0.2 g; 0.53 mmol) and (RS)-1-phenylethylamine (0.65 g;
5.4 mmol) after a reaction time of 15 hours at 150.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl2/ethyl acetate 1+1). M.p. 145.degree. C.
[0402] IR (ATR): 3028, 1606, 1546, 1494, 1450, 1221 (C--F), 1157,
837, 813, 697 cm.sup.-1
[0403] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 1.44 (d, 3H, 6.8 Hz,
CH.sub.3), 4.22 (s, 2H, CH.sub.2), 6.44-6.54 (m, 2H,
C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.04-7.35 (m, 9H, Ph and
4-F-Ph), 7.80 (d, 1H, 5.4 Hz, C.sup.6--H 2-amino-Pyr)
{4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]pyridin-2-yl}-(4--
methoxybenzyl)amine (26e)
[0404] Using the general method C, the title compound was obtained
from 26a (0.2 g; 0.5 mmol) and 4-methoxybenzylamine (2.0 g; 14.6
mmol) after a reaction time of 22 hours under reflux and separation
by column chromatography (Al.sub.2O.sub.3, CH.sub.2Cl.sub.2/ethyl
acetate 1+1). M.p. 196-200.degree. C.
[0405] IR (ATR): 1605, 1574, 1507, 1245, 1225 (C--F), 843, 814,
698
[0406] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 4.29 (s, 2H
isomers "A"+"B", NCH.sub.2), 4.35 (s, 2H "A"+"B", SCH2), 6.43-6.47
(m, 1H "A"+2H "B", C.sup.5--H "A" and C.sup.3--/C.sup.5--H "B"
2-amino-Pyr), 6.65 (s, 1H "A", C.sup.3--H2-amino-Pyr), 6.80-6.84
(m, 2H "A"+"B", 4-MeO-Ph), 7.14-7.51 (m, 11H "A"+"B", 4-MeO-Ph, Ph
and 4-F-Ph), 7.79 (d, 1H "B", 5.4 Hz, C.sup.6--H 2-amino-Pyr), 7.91
(d, 1H "A", 5.4 Hz, C.sup.6--H 2-amino-Pyr), 12.67 (bs, 1H,
exchangeable, lmidazole-NH), amino-NH not visible
4-[2-Benzylsulfanyl-5-(4-fluorophenyl)-3H-imidazol-4-yl]-2-methoxypyridine
(26f)
[0407] A suspension of 25a (0.1 g; 0.25 mmol) in methanolic
NaOCH.sub.3 solution (30%, 2 ml) was diluted with methanol (5 ml)
and stirred under reflux for 13 h. The reaction mixture was diluted
with H.sub.2O and the aqueous solution was extracted with
CH.sub.2Cl.sub.2 (3.times.). The combined organic extract was
washed with saturated NaCl solution, dried over Na.sub.2SO.sub.4
and concentrated. The oily residue was purified by column
chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/ethyl acetate
1+1).
[0408] .sup.1H-NMR (CDCl.sub.3): .delta. (ppm) 3.91 (s, 3H,
OCH.sub.3), 4.29 (s, 2H, CH.sub.2), 6.91-6.95 (m, 1H, 2-MeO-Pyr),
7.02-7.11 (m, 2H, 4-F-Ph), 7.27-7.38 (m, 7H, Ph and 4-F-Ph), 8.05
(d, 1H, 5.4 Hz, C.sup.6--H 2-MeO-Pyr), NH not visible
EXAMPLE 27
2-Chloro-4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imid-
azol-4-yl]pyridine (27a)
[0409] NaH (55-65%; 0.1 g; about 2 mmol) was introduced into a
solution of 24a (0.31 g; 1.0 mmol) in absolute THF (15 ml). The
initial charge was stirred at room temperature for 5 min, and
4-methylsulfinylbenzyl chloride (3, 0.19 g; 1.0 mmol) was added.
The reaction mixture was stirred at room temperature for 2 h. The
yellow-brown solution was diluted with H.sub.2O and neutralized
with 10% strength citric acid. The THF was removed and the aqueous
solution was extracted with ethyl acetate (2.times.). The combined
organic extract was washed with saturated NaCl solution (2.times.),
dried over Na.sub.2SO.sub.4 and concentrated. The solids residue
was purified by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/EtOH 9.5+0.5). M.p. 179.degree. C.
[0410] IR (ATR): 3049, 1592, 1505, 1374, 1224 (C--F), 1086, 1030
(S.dbd.O), 1014, 989, 839, 816, 781 cm.sup.-1 (C--Cl)
[0411] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.71 (s, 3H,
CH.sub.3), 4.48 (s, 2H, CH.sub.2), 7.25-8.24 (m, 10H, 2-Cl-Pyr,
4-MeS(O)-Ph and 4-F-Ph), 8.26 (d, 1H, 5.3 Hz, C.sup.6--H 2-Cl-Pyr),
12.94 (bs, 1H, exchangeable, NH)
2-Fluoro-4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imid-
azol-4-yl]pyridine (27b)
[0412] Using the general method A, the title compound was obtained
from 24b (4.2 g; 14.5 mmol) and 3 (4.1 g; 22 mmol) after a reaction
time of 2 hours and separation by column chromatography (1.
Al.sub.2O.sub.3, CH.sub.2Cl.sub.2/ethyl acetate 1+1, 2. SiO.sub.2
60, CH.sub.2Cl.sub.2/EtOH 9+1). M.p. 150.degree. C.
[0413] IR (ATR): 3061, 1610, 1506, 1408, 1227 (C--F), 1030
(S.dbd.O), 1016, 995, 978, 882, 839, 815 cm.sup.-1
[0414] .sup.1H-NMR (DMSO-d.sub.6): .delta. (ppm) 2.71 (s, 3H,
CH.sub.3), 4.49 (s, 2H, CH.sub.2), 7.10 (s, 1H, C.sup.3--H2-F-Pyr),
7.30-7.37 (m, 3H, C.sup.5--H 2-F-Pyr and 4-F-Ph), 7.47-7.67 (m, 6H,
4-F-Ph and 4-MeS(O)-Ph), 8.11 (d, 1H, 4,8 Hz, C.sup.6--H 2-F-Pyr),
12.95 (bs, 1H, exchangeable, NH)
Benzyl-4-[5-(4-fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidaz-
ol-4-yl]pyridin-2-yl}amine (27c)
[0415] Using the general method C, the title compound was obtained
from 27b (0.3 g; 0.68 mmol) and benzylamine (0.75 g; 7.0 mmol)
after a reaction time of 7 hours at 170.degree. C. and separation
by column chromatography (SiO.sub.2 60, CH.sub.2Cl.sub.2/ethanol
19+1).
[0416] M.p. 149.degree. C.
[0417] IR (ATR): 3238, 3064, 1600, 1558, 1514, 1495, 1227 (C--F),
1034 (S.dbd.O), 1006, 982, 839, 814 cm.sup.-1
[0418] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 2.70 (s, 3H,
CH.sub.3), 4.21 (s, 2H, NCH.sub.2), 4.32 (s, 2H, SCH.sub.2)
6.51-6.55 (m, 2H, C.sup.3--/C.sup.5--H 2-amino-Pyr), 7.03-7.42 (m,
13H. Ph, 4-MeS(O)-Ph and 4-F-Ph), 7.82 (d, 1H, 5.5 Hz, C.sup.6--H
2-amino-Pyr)
(RS)-{4-[5-(4-Fluorophenyl)-2-(4-methanesulfinylbenzylsulfanyl)-3H-imidazo-
l-4-yl]pyridin-2-yl}-(1-phenylethyl)amine (27d)
[0419] Using the general method C, the title compound was obtained
from 27b (0.3 g; 0.68 mmol) and (RS)-1-phenylethylamine (0.85 g;
7.0 mmol) after a reaction time of 10 hours at 170.degree. C. and
separation by column chromatography (SiO.sub.2 60,
CH.sub.2Cl.sub.2/ethanol 9+1). M.p. 193.degree. C.
[0420] IR (ATR): 2967, 1606, 1547, 1502, 1221 (C--F), 1085, 1031
(S.dbd.O), 1014, 838, 814, 670 cm.sup.-1
[0421] .sup.1H-NMR (CD.sub.3OD): .delta. (ppm) 1.45 (d, 3H, 6.8 Hz,
CH.sub.3), 2.67 (s, 3H, S(O)CH.sub.3), 4.28 (s, 2H, CH.sub.2),
4.62-4.73 (m, 1H, methyne-H), 6.42-6.53 (m, 2H,
C.sup.3--/C.sup.5--H 2-amino 7.09-7.44 (m, 9H, Ph and 4-F-Ph), ),
8.21 (d,1 H, 5.0 Hz, C.sup.6--H 2-F-Pyr).
[0422] Compounds obtained by method C are compiled in Table 3 below
(however, compound no. 31 was obtained by method D): TABLE-US-00003
TABLE 3 1H-NMR ##STR38## Example .sup.1H-NMR spectrum No. R.sup.3
Solvent .delta.(ppm) 28 ##STR39## DMSO-d6 2.59 (s, 3H, --SCH3),
4.59 (t, 2H, J=4.74 Hz, >N--CH2--), 6.46-6.71 (m, 2H, C3-/C5-H
2- amino-Pyr), 6.91-6.94 (m, 2H, thiophene), 7.07 (t, 1H,
exchangeable, J=4.7 Hz, Pyr-NH--), 7.16-7.23 (m, 1H, thiophene),
7.28-7.35 (m, 2H, 4-F-Phe), 7.41-7.50 (m, 2H, 4-F-Phe), 7.82-7.96
(m, 1H, C6-H 2-amino-Pyr), # 12.61 (s, 1H, exchangeable,
imidazole-NH) 29 ##STR40## DMSO-d6 2.60 (s, 3H, --SCH3), 4.41 (d,
2H, J=5.74 Hz, >N--CH2--), 6.17 (d, 1H, J=3.12 Hz, C3-H furan),
6.34-6.37 (m, 1H, C4-H furan), 6.46-6.49 (m, 1H, C5-H 2-amino-Pyr),
6.65 (s, 1H, # C3-H 2-amino-Pyr), 6.95 (t, 1H, J=6.00 Hz,
Pyr-NH--), 7.18-7.27 (m, 2H, 4-F-Phe), 7.44-7.55 (m, 3H, C5-H furan
and 4-F-Phe), 7.88 (d, 1H, J=4.70 Hz, C6-H 2-amino-Pyr), 12.62 (s,
1H, imidazole-NH) 30 ##STR41## DMSO-d6 1.47-1.53 (m, 1H, C3-H
tetrahydrofuran), 1.75-1.88 (m, 3H, C3-/C5-H tetrahydrofuran), 2.59
(s, 3H, --SCH3), 3.20-3.28 (m, 2H, >N--CH2--), 3.55-3.61 (m, 1H,
C5-H # tetrahydrofuran), 3.69-3.76 (m, 1H, C5-H tetrahydrofuran),
3.89-3.93 (m, 1H, methyne-H tetrahydrofurfurylamine), 6.39-6.68 (m,
3H, C3-/C5-H 2-amino-Pyr and Pyr-NH-- (1H exchangeable)), 7.15-7.31
(m, 2H, 4-F-Phe), 7.41-7.50 (m, 2H, 4-F-Phe), 7.76-7.92 (m, 1H,
C6-H 2-amino-Pyr), 12.58 (s, 1H, exchangeable, imidazole-NH) 31
##STR42## CD3OD 2.6 (s, 3H, --SCH3), 4.54 (s, 2H, >N--CH2--),
6.60 (d, 2H, J=4.16 Hz, C3-/C5-H 2 amino-Pyr), 7.03-7.12 (m, 2H,
4-F-Phe), 7.27-7.44 (m, 4H, C3-/C5-H 2-(aminomethyl)pyridine # and
4-F-Phe), 7.71-7.80 (m, 1H, C4-H 2-(aminomethyl)pyridine), 7.84 (d,
1H, J=6.04 Hz, C6-H 2-amino-Pyr), 8.43-8.46 (m, 1H, C6-H
2-(aminomethyl)pyridine) 32 ##STR43## CD3OD 2.60 (s, 3H, --SCH3),
4.48 (s, 2H, >N--CH2--), 6.59-6.62 (m, 2H, C3-/C5-H
2-amino-Pyr), 7.06-7.14 (m, 2H, 4-F-Phe), 7.34-7.45 (m, 3H, 4-F-Phe
and C5-H # 3-(aminomethyl)pyridine), 7.73-7.78 (m, 1H, C4-H
3-(aminomethyl)pyridine), 7.84 (d, 1H, J=6.18 Hz, C6-H
2-amino-Pyr), 8.37-8.40 (m, 1H, C6-H 3-(aminomethyl)pyridine),
8.44-8.45 (m, 1H, C2-H 3-(aminomethyl)pyridine) 33 ##STR44##
DMSO-d6 CD3OD 0.78-0.92 (m, 2H, cyclohexane), 1.10-1.22 (m, 3H,
cyclohexane), 1.42-1.45 (m, 1H, methyne-H, cyclohexylmethylamine),
1.64-1.70 (d, 5H, J=10.49 Hz, cyclohexane), 2.59 (s, 3H, --SCH3),
2.93-3.02 (m, 2H, >N--CH2--), 6.39-6.60 (m, 3H, C3-/C5-H
2-amino-Pyr and Pyr-NH--, # (1H exchangeable)), 7.12-7.31 (m, 2H,
4-F-Phe), 7.40-7.53 (m, 2H, 4-F-Phe), 7.76-7.91 (m, 1H, C6-H
2-amino-Pyr), 12.60 (s, 1H, exchangeable, imidazole-NH) 0.93 (t,
2H, J=11.05 Hz, cyclohexane), 1.17-1.28 (m, 3H, cyclohexane),
1.40-1.49 (m, 1H, methyne-H, cyclohexane), 1.75 (d, 5H, J=11.47 Hz,
cyclohexane), 2.62 (s, 3H, # --SCH3), 2.96-2.99 (m, 2H,
>NH--CH2--), 6.54 (d, 2H, J=5.10 Hz, C3-/C5-H 2-amino-Pyr), 7.14
(t, 2H, J=8.77 Hz, 4-F-Phe), 7.43-7.50 (m, 2H, 4-F-Phe), 7.80 (d,
1H, J=5.52 Hz, C6-H 2-amino-Pyr) 34 ##STR45## CD3OD 1.75-1.86 (m,
1H, C3-H 1-aminoindane), 2.45-2.53 (m, 1H, C3-H 1-aminoindane),
2.61 (s, 3H, --SCH3), 2.82-32.96 (m, 2H, C2-H, 1-aminoindane), 5.25
(t, 1H, J=7.29 Hz, methyne-H # 1- aminoindane), 6.56-6.59 (m, 1H,
C5-H 2-amino-Pyr), 6.67 (s, 1H, C3-H 2-amino-Pyr), 7.07-7.25 (m,
6H, C4-/C5-/C6-/C7-H 1-aminoindane and 4-F-Phe), 7.42-7.49 (m, 2H,
4-F-Phe), 7.84-7.87 (m, 1H, C6-H 2-amino-Pyr) 35 ##STR46## CD3OD
2.62 (s, 3H, --SCH3), 3.04 (t, 2H, J=7.02 Hz, --CH2--
2-(2-thienyl)ethylamine)), 3.47 (t, 2H, J=7.04 Hz, >N--CH2--
2-(2-thienyl)ethylamine)), 6.56-6.59 (m, 2H, C3-/C5-H #
2-amino-Pyr), 6.83-6.85 (m, 1H, C3-H thiophene), 6.89-6.94 (m, 1H,
C4-H thiophene), 7.09-7.20 (m, 3H, 4-F-Phe and C5-H thiophene),
7.43-7.50 (m, 2H, 4-F-Phe), 7.84 (d, 1H, J=6.12 Hz, C6-H
2-amino-Pyr) 36 ##STR47## CD3OD 2.58 (s, 3H, --SCH3), 3.00-3.03 (m,
2H, --CH2-- 1,2-diphenylethylamine), 4.73 (t, 1H, J=7.20 Hz,
methyne-H 1,2-diphenylethylamine), 6.40 (s, 1H, C3-H 2-amino-Pyr),
6.55 (d, 1H, J=5.44 Hz, C5-H 2-amino-Pyr), 7.05-7.40 (m, 14H,
4-F-Phe and Ar-H 1,2 diphenylethylamine), 7.77 (d, 1H, J=5.44 Hz,
C6-H 2-amino-Pyr)
EXAMPLE 37a
Cyclohexyl-{4-[5-(4-fluorophenyl)-2-methylsulfanyl-1H-imidazol-4-yl]pyridi-
n-2-yl}amine (37a)
[0423] 2-Fluoro-4-[5-(4-fluorophenyl)-2-methylsulfanyl-1
H-imidazol-4-yl]pyridine (1.2 g, 4 mmol), which had been weighed
out into a 25 ml one-necked flask which had been flushed with argon
beforehand, was suspended in cyclohexylamine (3.97 g, 0.04 mol),
covered with argon and then heated with reflux of the amine, in an
oil bath at a temperature of 160.degree. C., for 48 h. The brown
suspension is allowed to cool to RT. 30 ml of Na citrate solution
(10% strength citric acid solution pH 5 with conc. NaOH) are then
added, and the mixture is stirred for 10 min. and extracted twice
with 30 ml of ethyl acetate.
[0424] The combined organic phases are extracted twice again with
in each case 30 ml of Na citrate solution (10% strength citric acid
solution pH 5 with conc. NaOH) and then with 30 ml of NaHCO.sub.3
solution and extracted once with saturated NaCl solution. The
organic phase is dried over Na.sub.2SO.sub.4 and concentrated using
a rotary evaporator, and the residue is crystallized from 10
ml.
[0425] Recrystallization is carried out from isopropanol/water
(about 5 ml of ISOH are heated and allowed to cool, and about 5 ml
of dist. water are added slowly). Yield: 0.76 g (49.7%) of a purity
(HPLC) of 96.6%.
[0426] The compounds of the formula I compiled in Table 4 below are
obtained using this method: TABLE-US-00004 TABLE 4 Ex. Method Name
Structure 37b C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-methoxypyridine ##STR48## 37c C
Cyclohexyl-{4-[5-(4-fluorophenyl)-
2-isopropylsulfanyl-1H-imidazol-4- yl]pyridine-2-yl}amine ##STR49##
37d C Cyclohexyl-{4-[5-(4-fluorophenyl)-
2-(2,2,2-trifluoro-ethylsulfanyl)-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR50## 37e C
Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}-amine ##STR51## 37f C
Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-ethylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR52## 37g C
Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-isopropylsulfanyl-
1H-imidazol-4-yl]pyridin-2-yl}amine ##STR53## 37h C
Cyclohexyl-{4-[5-(2,4- difluorophenyl)-2-(2,2,2-trifluoro-
ethylsulfonyl)-1H-imidazol-4- yl]pyridin-2-yl}amine ##STR54## 37i C
Cyclohexyl-{4-[2-methylsulfanyl-5- (3-trifluoromethylphenyl)-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR55## 37j C
Cyclohexyl-{4-[2-ethylsulfanyl-5- (3-trifluoromethylphenyl)-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR56##
[0427] The compounds compiled in Table 5 below were obtained using
the above method: TABLE-US-00005 TABLE 5 Ex. Process Name Structure
38 G 4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
pyridin-2-ylamine ##STR57## 39 C Methyl-{4-[5-(4-fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine ##STR58## 40 C
Ethyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}amine ##STR59## 41 C
Isopropyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}amine ##STR60## 42 C Methoxyethyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR61## 43 C N,N-Dimethylaminoethyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR62## 44 C Hydroxypropyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR63## 45 C N'-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-N,N-
diphenylethane-1,2-diamine ##STR64## 46 H
Cinnamyl-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}amine ##STR65## 47 C Cyclopropyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR66## 48 C Cyclopropylmethyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR67## 49 C Cycloheptyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR68## 50 C Bicyclo[2.2.1]hept-2-yl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR69## 51 C Adamantan-1-yl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR70## 52 C Adamantan-2-yl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR71## 53 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- pyridin-2-yl}-(tetrahydrofuran-3-
yl)-amine ##STR72## 54 H {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- pyridin-2-yl}-(tetrahydropyran-4-
yl)amine ##STR73## 55 C (1-Ethylpyrrolidin-2-ylmethyl)-{4-
[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}amine ##STR74## 56 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-(2-piperidin-1-
ylethyl)amine ##STR75## 57 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-(2-morpholin-4-
ylethyl)amine ##STR76## 58 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-(1-methylpiperidin-
4-yl)-amine ##STR77## 59 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-[2-(4-
methylpiperazin-1-yl)ethyl]amine ##STR78## 60 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(1-naphthalen-2- ylethyl)amine ##STR79## 61 H
2,2-Diphenylethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR80## 62 H
Biphenyl-2-ylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR81## 63 H
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(3- phenylpropyl)amine ##STR82## 64 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-indan-2-ylamine ##STR83## 65 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(1,2,3,4- tetrahydronaphthalen-1-yl)amine
##STR84## 66 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-(1,2,3,4-
tetrahydronaphthalen-2-yl)amine ##STR85## 67 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}quinolin-2- ylmethylamine ##STR86## 68 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl]pyridin-4- ylmethylamine ##STR87## 69 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-quinolin-4- ylmethylamine ##STR88## 70 H
[1-(5-Chlorothiophen-2-yl)ethyl]- {4-[5-(4-fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine ##STR89## 71 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-thiophen-3- ylmethylamine ##STR90## 72 C
Benzo[b]thiophen-2-ylmethyl-{4- [5-(4-fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}amine ##STR91## 73 C
Benzofuran-2-ylmethyl-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR92## 74 H
(1-Benzofuran-2-yl-ethyl)-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR93## 75 C (2,3-Dihydrobenzofuran-2-
ylmethyl)-{4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridine-2-yl}amine ##STR94## 76 C {4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-oxazol-2-
ylmethylamine ##STR95## 77 C Benzoxazol-2-ylmethyl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR96## 78 C 2-({4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-ylamino}methyl)-4-
isopropyloxazol-5-ol ##STR97## 79 C N-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-N'-(2-
methylsulfanylvinyl)formamidine ##STR98## 80 C
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-N'-(1-methyl-2- methylsulfanylpropenyl)formamidine
##STR99## 81 C N-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}-N'-(2-methyl-
sulfanylphenyl)formamidine ##STR100## 82 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(2-methylthiazol-5- ylmethyl)amine ##STR101## 83 C
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(2-methylthiazol-4- ylmethyl)amine ##STR102## 84 C
{4-[5-(4-Fluorophenyl)-2-methyl- sulfanyl-1H-imidazol-4-yl]pyridin-
2-yl}-[2-(2-methyleneamino- phenylsulfanyl)-ethyl]amine ##STR103##
85 B 2-Bromo-4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridine ##STR104## 86 G 2-Azido-4-[5-(4-fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridine ##STR105## 87 D
2-Ethoxy-4-[5-(4-fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridine ##STR106## 88 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-p-tolyloxypyridine ##STR107##
89 C 2-(2.6-Dichlorophenoxy)-4-[5-(4-
fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridine
##STR108## 90 D 2-Benzyloxy-4-[5-(4-
fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridine
##STR109## 91 D 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-phenethyloxypyridine ##STR110##
92 D 2-Cyclohexyloxy-4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridine ##STR111## 93 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]-
2-(tetrahydrofuran-3-yloxy)pyridine ##STR112## 94 D
6-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yloxy}hexa- hydrofuro[3.2-b]furan-3-ol ##STR113## 95 C
4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
2-(tetrahydrofuran-2- ylmethoxy)pyridine ##STR114## 96 C
4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
2-(tetrahydropyran-2-ylmethoxy)- pyridine ##STR115## 97 C
2-(Benzofuran-2-ylmethoxy)-4-[5- (4-fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridine ##STR116## 98 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-(furan-2-ylmethoxy)pyridine
##STR117## 99 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-(thiophen-2-ylmethoxy)pyridine
##STR118## 100 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-(5-chlorothiophen-2-yl-
methoxy)pyridine ##STR119## 101 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-(thiophen-3-ylmethoxy)pyridine
##STR120## 102 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-(thiazol-2-ylmethoxy)pyridine
##STR121## 103 C Bicyclo[2.2.1]hept-2-yl-{4-[5-(4-
fluorophenyl)-2-methylsulfanyl-1H- imidazol-4-yl]pyridin-2-yl}amine
##STR122## 104 C 3-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yloxy}-1-
azabicyclo[2.2.2]octane ##STR123## 105 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-methylsulfanylpyridine
##STR124## 106 C 2-Benzenesulfonyl-4-[5-(4-
fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridine
##STR125## 107 C 4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4-yl]- 2-phenylsulfanylpyridine
##STR126## 108 C 2-Ethylsulfanyl-4-[5-(4-
fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridine
##STR127## 109 C 2-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-ylsulfanyl}ethanol
##STR128## 110 C 3-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-ylsulfanyl]propan-1-ol
##STR129## 110a E N-{4-[5-(4-Fluorophenyl)-2-
methylsulfanyl-1H-imidazol-4- yl]pyridin-2-yl}formamide ##STR130##
111 E N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}benzamide ##STR131## 112 E
4-Chloro-N-{4-[5-(4-fluorophenyl)- 2-methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}benzamide ##STR132## 113 E
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-3- methylbenzamide ##STR133## 114 E
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-3- trifluoromethylbenzamide ##STR134## 115 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-2-phenylacetamide ##STR135## 116 F
Cyclohexanecarboxylic acid {4-[5-
(4-fluorophenyl)-2-methylsulfanyl- 1H-imidazol-4-yl]pyridin-2-
yl}amide ##STR136##
117 F 2-Cyclohexyl-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridin-2- yl}acetamide ##STR137## 118 F
2-(4-Chlorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridin-2- yl}acetamide ##STR138## 119 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-2-(4- methoxyphenyl)acetamide ##STR139## 120 F
2-(4-Fluorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-1H-
imidazol-4-yl]pyridin-2-yl}acetamide ##STR140## 121 F
2-(2-Fluorophenyl)-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridin-2- yl}acetamide ##STR141## 122 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-yl]-
pyridin-2-yl}-3-phenylpropionamide ##STR142## 123 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-3-phenylacrylamide ##STR143## 124 F
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-carbamic acid benzyl ester ##STR144## 125 F
1-Benzoyl-3-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridin-2-yl}urea ##STR145## 126 E
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl]acetamide ##STR146## 127 F
2.2,2-Trifluoro-N-{4-[5-(4- fluorophenyl)-2-methylsulfanyl-
1H-imidazol-4-yl]pyridin-2- yl}acetamide ##STR147## 128 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-2- methoxyacetamide ##STR148## 129 F
N-{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-2- (methylphenylamino)acetamide ##STR149## 130 F
{4-[5-(4-Fluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-carbamic acid cyclohexyl ester ##STR150## 131 C
{4-[5-(2,4-Difluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}isopropylamine ##STR151## 132 C
{4-[5-(2,4-Difluorophenyl)-2- ethylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}isopropylamine ##STR152## 133 C
{4-[5-(2,4-Difluorophenyl)-2- isopropylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}isopropylamine ##STR153## 134 F
Isopropyl-{4-[2-methylsulfanyl-5- (3-trifluoromethylphenyl)-1H-
imidazol-4-yl]pyridin-2-yl}amine ##STR154## 135 F
{4-[2-Ethylsulfanyl-5-(3- trifluoromethylphenyl)-1H-
imidazol-4-yl]pyridin-2- yl}isopropylamine ##STR155## 136 F
{4-[5-(2,4-Difluorophenyl)-2- methylsulfanyl-1H-imidazol-4-
yl]pyridin-2-yl}-(2- methoxyethyl)amine ##STR156## 137 F
{4-[5-(4-Fluorophenyl)-2- methylsulfonyl-1H-imidazol-4-
yl]pyridin-2-yl}urea ##STR157## 138 F N-{4-[5-(4-Fluorophenyl)-2-
methylsulfonyl-1H-imidazol-4- yl]pyridin-2-yl-2-(4-
isobutylphenyl)propionamide ##STR158##
* * * * *